The proposal that chromosomes carried the factors of Mendelian inheritance was initially controversial, but in 1905 it gained
strong support when  Nettie Stevens  showed that the "accessory chromosome" of mealworms' sperm cells was decisive in the sex identity of the progeny, [ 12 ] [ 13 ]  a discovery supported by her mentor  E.B. Wilson . [ 14 ]  Later,  Eleanor Carothers  documented definitive evidence of  independent assortment  of chromosomes in a species of grasshopper. [ 15 ]   Debate continued, however, until 1915 when  Thomas Hunt Morgan 's work on inheritance and  genetic linkage  in the fruit fly  Drosophila melanogaster  provided incontrovertible evidence for the proposal. [ 1 ] [ better source needed ] [ 3 ]  The unifying theory stated that inheritance patterns may be generally explained by assuming that genes are located in specific sites on chromosomes.


Herbert Wayne  " Herb "  Boyer  (born July 10, 1936) is an American biotechnologist, researcher and entrepreneur in biotechnology. Along with  Stanley N. Cohen  and  Paul Berg , he discovered  recombinant DNA , a method to coax bacteria into producing foreign proteins, which aided in jump-starting the field of  genetic engineering . By 1969, he had performed studies on a couple of restriction enzymes of  E. coli  with especially useful properties.


He is recipient of the 1990  National Medal of Science , co-recipient of the 1996  Lemelson–MIT Prize , and a co-founder of  Genentech . He was professor at the  University of California, San Francisco  (UCSF) and later served as vice president of Genentech from 1976 until his retirement in 1991. [ 1 ]


Herbert Boyer was born in 1936 in  Derry, Pennsylvania . He received his  bachelor's degree  in biology and chemistry from  Saint Vincent College  in  Latrobe, Pennsylvania , in 1958. He married his wife Grace the following year. He received his  PhD  at the  University of Pittsburgh  in 1963 and participated as an activist in the  civil rights  movement.


Boyer spent three years in postdoctoral work at  Yale University  in the laboratories of Professors Edward Adelberg and Bruce Carlton, and then became an assistant professor at the  University of California, San Francisco  and a professor of biochemistry from 1976 to 1991, where he discovered that genes from bacteria could be  combined  with genes from  eukaryotes . In 1977, Boyer's laboratory and collaborators  Keiichi Itakura  and  Arthur Riggs  at  City of Hope National Medical Center  described the first-ever synthesis and expression of a peptide-coding gene. [ 2 ]  In August 1978, he produced synthetic  insulin  using his new transgenic  genetically modified bacteria , followed in 1979 by a  growth hormone .


In 1976, Boyer founded  Genentech  with  venture capitalist   Robert A. Swanson .  Genentech's approach to the first synthesis of  insulin  won out over  Walter Gilbert 's approach at  Biogen  which used whole  genes  from natural sources. Boyer built his gene from its individual  nucleotides .


In 1990, Boyer and his wife Grace gave the single largest donation ($10,000,000) bestowed on the  Yale School of Medicine  by an individual. The Boyer Center for Molecular Medicine was named after the Boyer family in 1991. [ 3 ] [ 4 ]


At the Class of 2007 Commencement, St. Vincent College announced that they had renamed the School of Natural Science, Mathematics, and Computing the Herbert W. Boyer School. [ 5 ]


Among his professional activities, Boyer is on the board of directors of  Scripps Research . [ 6 ]


Sydney Brenner   CH   FRS   FMedSci   MAE  (13 January 1927 – 5 April 2019) [ 13 ] [ 14 ]  was a  South African   biologist . In 2002, he shared the  Nobel Prize in Physiology or Medicine  with  H. Robert Horvitz  and Sir  John E. Sulston . [ 10 ]  Brenner made significant contributions to work on the  genetic code , and other areas of molecular biology while working in the  Medical Research Council  (MRC)  Laboratory of Molecular Biology  in  Cambridge , England. He established the  roundworm   Caenorhabditis elegans  as a  model organism  for the investigation of  developmental biology , [ 11 ] [ 15 ]  and founded the  Molecular Sciences Institute  in  Berkeley ,  California , United States. [ 16 ] [ 17 ] [ 18 ] [ 19 ] [ 20 ] [ 21 ] [ 22 ] [ 23 ]


Brenner was born in the town of  Germiston  in the then  Transvaal  (today in  Gauteng ), South Africa, on 13 January 1927. [ 2 ]  His parents, Leah [ 24 ]  (née Blecher) and Morris Brenner, were  Jewish   immigrants . His father, a cobbler, came to South Africa from  Lithuania  in 1910, and his mother from  Riga , Latvia, in 1922. He had one sister, Phyllis. [ 25 ] [ 26 ]


He was educated at  Germiston High School [ 2 ]  and the  University of the Witwatersrand . Having joined the university at the age of 15, it was noted during his second year that he would be too young to qualify for the practice of medicine at the conclusion of his six-year medical course, and he was therefore allowed to complete a  Bachelor of Science  degree in  Anatomy  and  Physiology . During this time he was taught physical chemistry by  Joel Mandelstam , microscopy by  Alfred Oettle  and neurology by  Harold Daitz . He also received an introduction to anthropology and paleontology from  Raymond Dart  and  Robert Broom . The histologist  Joseph Gillman  and director of research in the Anatomy Department persuaded Brenner to continue towards an honours degree and beyond towards an MSc. Brenner accepted though this would mean he would not graduate from medical school and his bursary would be discontinued. He supported himself during this time by working as a laboratory technician. It was during this time, in 1945, that Brenner would publish his first scientific works. His masters thesis was in the field of  cytogenetics  and publications during this time in the field Brenner would later call  Cell Physiology . [ 25 ]


In 1946  Wilfred Le Gros Clark  invited Brenner to his Department of Anatomy in Oxford, during a visit to South Africa. Brenner was persuaded to finish his medical education instead. Brenner returned to medical school where he failed Medicine, nearly failed Surgery and achieved a First Class in Obstetrics and Gynecology. Six months later Brenner had finished repeating Medicine and Surgery and in 1951 received the degrees of  Bachelor of Medicine, Bachelor of Surgery  (MBBCh). [ 25 ]


Brenner received an  1851 Exhibition Scholarship  from the  Royal Commission for the Exhibition of 1851  which enabled him to complete a  Doctor of Philosophy (DPhil) [ 7 ]  degree at the  University of Oxford  as a postgraduate student of  Exeter College, Oxford , supervised by  Cyril Hinshelwood . [ 27 ]


Following his DPhil, Brenner did  postdoctoral research  at the  University of California, Berkeley . [ 28 ]  He spent the next 20 years at the  Laboratory of Molecular Biology [ 29 ]  in Cambridge. There, during the 1960s, he contributed to molecular biology, then an emerging field. In 1976 he joined the  Salk Institute  in  California . [ 2 ]


Together with  Jack Dunitz ,  Dorothy Hodgkin ,  Leslie Orgel , and  Beryl M. Oughton , he was one of the first people in April 1953 to see the model of the structure of  DNA , constructed by  Francis Crick  and  James Watson ; at the time he and the other scientists were working at the  University of Oxford 's Chemistry Department. All were impressed by the new DNA model, especially Brenner, who subsequently worked with Crick in the  Cavendish Laboratory  at the  University of Cambridge  and the newly opened  Medical Research Council  (MRC)  Laboratory of Molecular Biology  (LMB). According to Beryl Oughton, later Rimmer, they all travelled together in two cars once  Dorothy Hodgkin  announced to them that they were off to Cambridge to see the model of the structure of DNA. [ 30 ]


Brenner made several seminal contributions to the emerging field of  molecular biology  in the 1960s (see  Phage group ). The first was to prove that all overlapping genetic  coding sequences  were impossible. This insight separated the coding function from structural constraints as proposed in a clever code by  George Gamow . This led Francis Crick to propose the concept of a hypothetical molecule  (later identified as  transfer RNA  or tRNA) that transfer the genetic information from RNA to proteins. Brenner gave the name " adaptor hypothesis " in 1955. [ 31 ]  The physical separation between the  anticodon  and the amino acid on a tRNA is the basis for the unidirectional flow of information in coded biological systems. This is commonly known as the  central dogma of molecular biology , i.e. information flows from nucleic acid to protein and never from protein to nucleic acid. Following this adaptor insight, Brenner conceived of the concept of  messenger RNA  during an April 1960 conversation with Crick and  François Jacob , and together with Jacob and  Matthew Meselson  went on to prove its existence later that summer. [ 32 ]  Then, with Crick,  Leslie Barnett , and Richard J. Watts-Tobin, Brenner genetically demonstrated the triplet nature of the code of  protein translation  through the  Crick, Brenner, Barnett, Watts-Tobin et al. experiment of 1961 , [ 33 ]  which discovered  frameshift mutations . Brenner collaborating with Sarabhai, Stretton and Bolle in 1964, using  amber mutants  defective in the  bacteriophage T4D  major head protein, showed that the  nucleotide sequence  of the  gene  is co-linear with the amino acid sequence of the encoded polypeptide chain. [ 34 ]


Together with the decoding work of  Marshall Warren Nirenberg  and others, the discovery of the triplet nature of the  genetic code  was critical to deciphering the code. [ 35 ]  Barnett helped set up Sydney Brenner's laboratory in  Singapore , many years later. [ 36 ] [ 37 ]


Brenner, with George Pieczenik, [ 38 ]  created the first computer matrix analysis of nucleic acids using TRAC, which Brenner continued to use. Crick, Brenner,  Klug  and Pieczenik returned to their early work on deciphering the genetic code with a pioneering paper on the origin of protein synthesis, where constraints on mRNA and tRNA co-evolved allowing for a five-base interaction with a flip of the anticodon loop, and thereby creating a triplet code translating system without requiring a  ribosome . This model requires a partially overlapping code. [ 39 ]  The published scientific paper is extremely rare in that its collaborators include three authors who independently became Nobel laureates. [ 40 ]


Brenner then focused on establishing a free-living roundworm  Caenorhabditis elegans  as a  model organism  for the investigation of animal  development  including  neural development . He chose this 1-millimeter-long soil  roundworm  mainly because it is simple, is easy to grow in bulk populations, and turned out to be quite convenient for genetic analysis. One of the key methods for identifying important function genes was the screen for roundworms that had some functional defect, such as being  uncoordinated , leading to the identification of new sets of proteins, such as the  UNC  proteins. For this work, he shared the 2002  Nobel Prize in Physiology or Medicine  with  H. Robert Horvitz  and  John Sulston . The title of his Nobel lecture in December 2002, "Nature's Gift to Science", is a homage to this  nematode ; in it, he considered that having chosen the right organism turned out to be as important as having addressed the right problems to work on. [ 41 ]  In fact, the  C. elegans  community has grown rapidly in recent decades with researchers working on a wide spectrum of problems. [ 42 ]


Brenner founded the  Molecular Sciences Institute  in  Berkeley, California  in 1996. [ 4 ]  As of 2015 [update]  he was associated with the  Salk Institute , the  Institute of Molecular and Cell Biology , the Singapore  Biomedical Research Council , the  Janelia Farm Research Campus , and the  Howard Hughes Medical Institute . [ 4 ]  In August 2005, Brenner was appointed president of the  Okinawa Institute of Science and Technology . [ 43 ]  He was also on the Board of Scientific Governors at  The Scripps Research Institute , [ 44 ]  as well as being Professor of Genetics there. [ 3 ]  A scientific biography of Brenner was written by  Errol Friedberg  in the US, for publication by  Cold Spring Harbor Laboratory  Press in 2010. [ 19 ]


Known for his penetrating scientific insight and acerbic wit, Brenner, for many years, authored a regular column ("Loose Ends") in the journal  Current Biology . [ 45 ] [ 46 ]  This column was so popular that "Loose ends from Current Biology", a compilation, was published by Current Biology Ltd. [ 47 ]  and became a collectors' item. Brenner wrote " A Life in Science ", [ 48 ]  a paperback published by  BioMed Central . He is also noted for his generosity with ideas and the great number of students and colleagues his ideas have stimulated. [ 49 ] [ 50 ] [ 51 ] [ 52 ]


In 2017, Brenner co-organized a seminal lecture series in Singapore describing ten logarithmic scales of time from the  Big Bang  to the present, spanning the appearance of multicellular life forms, the evolution of humans, and the emergence of language, culture and technology. [ 53 ]  Prominent scientists and thinkers, including  W. Brian Arthur ,  Svante Pääbo ,  Helga Nowotny  and  Jack Szostak , spoke during the lecture series. In 2018, the lectures were adapted into a popular science book titled  Sydney Brenner's 10-on-10: The Chronicles of Evolution , published by Wildtype Books. [ 54 ]


Brenner also gave four lectures on the history of molecular biology, its impact on neuroscience and the great scientific questions that lie ahead. [ 55 ]  The lectures were adapted into the book,  In the Spirit of Science: Lectures by Sydney Brenner on DNA, Worms and Brains . [ 56 ]


The "American plan" and "European plan" were proposed by Sydney Brenner as competing models for the way brain cells determine their neural functions. [ 16 ] [ 57 ] [ 58 ]  According to the European plan (sometimes referred to as the British plan), the function of cells is determined by their  genetic  lineage. According to the American plan, a cell's function is determined by the function of its neighbours after  cell migration . Further research has shown that most species follow some combination of these methods, albeit in varying degrees, to transfer information to new cells. [ 59 ] [ 60 ]


Brenner received numerous awards and honours, including: [ 61 ] [ 62 ]


Brenner was married to May Brenner ( née  Covitz , subsequently Balkind) [ 2 ]  from December 1952 until her death in January 2010; [ 2 ]  their children include Belinda, Carla, Stefan, and his stepson Jonathan Balkind from his wife's first marriage to Marcus Balkind. He lived in  Ely, Cambridgeshire . [ 70 ] [ 71 ]  He was an atheist. [ 72 ]


Brenner died on 5 April 2019, in Singapore, at the age of 92. [ 10 ] [ 73 ] [ 74 ]


Calvin Blackman Bridges  (January 11, 1889 – December 27, 1938) was an American scientist known for his contributions to the field of  genetics . Along with  Alfred Sturtevant  and  H.J. Muller , Bridges was part of  Thomas Hunt Morgan 's famous "Fly Room" at  Columbia University .


Calvin Blackman Bridges was born in  Schuyler Falls ,  New York  in 1889 to the parents of Leonard Bridges and Charlotte Blackman. Tragically, Calvin's mother died when he was two years old, and his father died a year later, leaving the young Calvin an orphan. Bridges was subsequently taken in and raised by his grandmother. It took Bridges several years to complete high school, graduating when he was 20 years old. Despite this setback, he moved on to be an outstanding student at  Columbia University  in  New York City , which he attended both undergraduate and postgraduate school.


While taking a  zoology  class at Columbia, Bridges met  Thomas Hunt Morgan . This started a relationship which would eventually lead to many important scientific discoveries regarding genetics and  evolution .


The "Fly Room" experiments began in 1910 and continued for seventeen years, with Thomas Hunt Morgan being the project's lead experimental developer. [ 1 ]  Among many others working alongside Bridges and Morgan in the laboratory were  Alfred Sturtevant  and  Hermann Joseph Muller . The "Fly Room" experiments were the first to use the common fruit fly  Drosophila melanogaster  for research in genetics, because they are cheap, easily accessible, and reproduce quickly. [ 2 ]  The experiments resulted in many important early discoveries in the field, resolved previously unclear issues such as the organization of genetic information within  chromosomes , chromosomal arrangement, and  linkage  in  sex chromosomes , and contributed to the emergence of modern treatments of genetics and  evolutionary biology  from their classical foundations, all in an era before  molecular biology  had yet revealed the structure or nature of  DNA . The group also contributed to the understanding of the impact of  mutations  on evolution in general. [ 2 ]  The success of the "Fly Room" experiments eventually made  D. melanogaster  a widely popular  model organism  for biological research of all types.


Bridges in particular was responsible for many improvements regarding the techniques and the equipment used in the experiments. He suggested the use binocular microscopes instead of hand lenses that had been using before, which improved data quality and convenience. Bridges also developed temperature controls for the experiments which proved to be more useful and yielded better results than the previous temperature controls. [ 1 ]


Bridges published many works, one of his most famous being "Sex in Relation to Chromosomes and Genes". [ 3 ]  He also contributed many items to the  Journal of Experimental Zoology  and  Science . His work with  sex-linked traits  suggested that chromosomes contained  genes ;  Nettie Maria Stevens  was later able to support this hypothesis by examining the chromosomes of the fruit flies. Bridges wrote a couple of papers presenting the proof. He thanked her as "Miss Stevens" without stating what her contribution was nor referring to her Ph.D. [ citation needed ]


Bridges' PhD thesis on " Non-disjunction  as proof of the chromosome theory of heredity" appeared as the first paper in the first issue of the journal  Genetics  in 1916. In this paper, he also established that the  Y chromosome  does not determine gender in  Drosophila . [ 4 ]  Bridges' best-known contribution among  Drosophila  researchers is his observation and documentation of the  polytene chromosomes  found in larval  salivary gland  cells. [ 5 ]  The banding patterns of these chromosomes are still used as genetic landmarks even by contemporary researchers. [ citation needed ]  Bridges was elected to the  National Academy of Sciences  in 1936 for his work with  Drosophila . [ 1 ]


After his death, Bridges' student  Katherine Brehme Warren  completed work on  The Mutants of Drosophila melanogaster  (1944), a classic book which was for two decades an indispensable resource for geneticists, with information from the "Red Book" later being transferred to the  FlyBase  database. [ 6 ]  Morgan and Sturtevant destroyed almost all of Bridges' notebooks after his death, except the four which were not in their possession. [ citation needed ]


Bridges married Gertrude Ives, with whom he had four children. He was known to be both brilliant and very kind and considerate, [ 1 ]  though he was equally well-known for his womanizing and his struggles to keep up with family obligations. [ 7 ]  He was an atheist. [ 8 ]  In 1938, Bridges died from what is believed to have been a case of  syphilis . [ citation needed ]


1. "Bridges, Calvin Blackman."  Complete Dictionary of Scientific Biography . Vol. 2. Detroit: Charles Scribner's Sons, 2008. 455-457. Gale Virtual Reference Library. Web. 26 January 2015.


2. Muhlrad, Paul J. "Fruit Fly: Drosophila."  Genetics . Ed. Richard Robinson. Vol. 2. New York: Macmillan Reference USA, 2003. 42-45. Gale Virtual Reference Library. Web. 26 January 2015.


3. "Bridges, Calvin Blackman."  Britannica Biographies  (2012): 1. Middle Search Plus. Web. 26 January 2015.


4. Gambis , Alexis, director. The Fly Room . Imaginal Disc, 2014.


The  Cambridge Reference Sequence  ( CRS ) for  human   mitochondrial DNA  was first announced in 1981. [ 2 ]


A group led by  Fred Sanger  at the  University of Cambridge  had sequenced the mitochondrial genome of one woman of European descent [ 3 ]  during the 1970s, determining it to have a length of 16,569 base pairs (0.0006% of the nuclear human genome) containing some 37 genes and published this sequence in 1981. [ 2 ]


When other researchers repeated the sequencing, some striking discrepancies were noted. The original published sequence included eleven errors, including one extra base pair in position 3107, and incorrect assignments of single base pairs. Some of these were the result of contamination with bovine and  HeLa  specimens. The corrected revised CRS was published by Andrews et al. in 1999. [ 4 ]  (The original nucleotide numbering was retained to avoid confusion.) The reference sequence belongs to European  haplogroup H2a2a1 . The revised CRS is designated as  rCRS . It is deposited in the GenBank NCBI database under accession number NC_012920. [ 1 ]


When  mitochondrial DNA sequencing is used for genealogical purposes , the results are often reported as differences from the revised CRS. The CRS is a reference sequence rather than a record of the earliest human mtDNA. A difference between a tested sample and the CRS may have arisen in the lineage of the CRS or in the lineage of the tested sample. [ citation needed ]  The CRS includes seven nucleotides that are rare  polymorphisms : 263A, 311C-315C, 750A, 1438A, 4769A, 8860A, and 15326A. [ 5 ]


An alternative African (Yoruba) reference sequence has also been used sometimes instead of the Cambridge. It has a different numbering system with a length of 16,571 base pairs and represents the mitochondrial genome of one African individual. Other alternative reference sequences that have also sometimes been used include the African (Uganda), Swedish and Japanese sequences. [ 6 ]


In 2012, it was proposed that the revised Cambridge Reference Sequence (rCRS), should be replaced by a new Reconstructed Sapiens Reference Sequence (RSRS). [ 7 ]  The RSRS keeps the same numbering system as the CRS, but represents the ancestral genome of  Mitochondrial Eve , from which all currently known human mitochondria descend. The RSRS should be more useful for comparing the changes in different haplogroups [ 3 ]  although this has been debated. [ 8 ]   Family Tree DNA  reports results for mtDNA for both rCRS and RSRS. [ 3 ]


The  central dogma of molecular biology  deals with the flow of genetic information within a biological system. It is often stated as "DNA makes RNA, and RNA makes protein", [ 1 ]  although this is not its original meaning. It was first stated by  Francis Crick  in 1957, [ 2 ] [ 3 ]  then published in 1958: [ 4 ] [ 5 ]


The Central Dogma. This states that once "information" has passed into  protein   it cannot get out again.  In more detail, the transfer of information from  nucleic acid  to nucleic acid, or from nucleic acid to protein may be possible, but transfer from protein to protein, or from protein to nucleic acid is impossible. Information here means the  precise  determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein.


He re-stated it in a  Nature  paper published in 1970: "The central dogma of  molecular biology  deals with the detailed  residue -by-residue transfer of  sequential information . It states that such information cannot be transferred back from protein to either protein or nucleic acid." [ 6 ]


A second version of the central dogma is popular but incorrect. This is the simplistic DNA → RNA → protein pathway published by  James Watson  in the first edition of  The Molecular Biology of the Gene  (1965). Watson's version differs from Crick's because Watson describes a two-step (DNA → RNA and RNA → protein) process as the central dogma. [ 7 ]  While the dogma as originally stated by Crick remains valid today, [ 6 ] [ 8 ]  Watson's version does not. [ 2 ]


The  biopolymers  that comprise DNA, RNA and (poly) peptides  are linear heteropolymers (i.e.: each  monomer  is connected to at most two other monomers). The  sequence  of their monomers effectively encodes information. The transfers of information from one molecule to another are faithful,  deterministic  transfers, wherein one biopolymer's sequence is used as a template for the construction of another biopolymer with a sequence that is entirely dependent on the original biopolymer's sequence. When DNA is transcribed to RNA, its complement is paired to it. DNA codes are transferred to RNA codes in a complementary fashion. The encoding of proteins is done in groups of three, known as  codons . The  standard codon table  applies for humans and mammals, but some other lifeforms (including human mitochondria [ 9 ] ) use different  translations . [ 10 ]


In the sense that DNA replication must occur if genetic material is to be provided for the  progeny  of any cell, whether  somatic  or  reproductive , the copying from DNA to DNA arguably is the fundamental step in information transfer. A complex group of proteins called the  replisome  performs the replication of the information from the parent strand to the complementary daughter strand.


Transcription is the process by which the information contained in a section of DNA is replicated in the form of a newly assembled piece of  messenger RNA  (mRNA). Enzymes facilitating the process include  RNA polymerase  and  transcription factors . In  eukaryotic  cells the primary transcript is  pre-mRNA . Pre-mRNA must be  processed  for translation to proceed. Processing includes the addition of a  5' cap  and a  poly-A tail  to the pre-mRNA chain, followed by  splicing .  Alternative splicing  occurs when appropriate, increasing the diversity of the proteins that any single mRNA can produce. The product of the entire transcription process (that began with the production of the pre-mRNA chain) is a mature mRNA chain.


The mature mRNA finds its way to a  ribosome , where it gets  translated . In  prokaryotic  cells, which have no nuclear compartment, the processes of transcription and translation may be linked together without clear separation. In  eukaryotic  cells, the site of transcription (the  cell nucleus ) is usually separated from the site of translation (the  cytoplasm ), so the mRNA must be transported out of the nucleus into the cytoplasm, where it can be bound by ribosomes. The ribosome reads the mRNA triplet  codons , usually beginning with an AUG ( adenine − uracil − guanine ), or initiator  methionine  codon downstream of the  ribosome  binding site. Complexes of  initiation factors  and  elongation factors  bring  aminoacylated   transfer RNAs  (tRNAs) into the ribosome-mRNA complex, matching the codon in the mRNA to the anti-codon on the tRNA. Each tRNA bears the appropriate  amino acid  residue to add to the  polypeptide  chain being synthesised. As the amino acids get linked into the growing peptide chain, the chain begins folding into the correct conformation. Translation ends with a  stop codon  which may be a UAA, UGA, or UAG triplet.


The mRNA does not contain all the information for specifying the nature of the mature protein. The nascent polypeptide chain released from the ribosome commonly requires additional processing before the final product emerges. For one thing, the correct folding process is complex and vitally important. For most proteins it requires other  chaperone proteins  to control the form of the product. Some proteins then excise internal segments from their own peptide chains, splicing the free ends that border the gap; in such processes the inside "discarded" sections are called  inteins . Other proteins must be split into multiple sections without splicing. Some polypeptide chains need to be cross-linked, and others must be attached to  cofactors  such as haem (heme) before they become functional.


Reverse transcription is the transfer of information from RNA to DNA (the reverse of normal transcription). This is known to occur in the case of  retroviruses , such as  HIV , as well as in  eukaryotes , in the case of  retrotransposons  and  telomere  synthesis.
It is the process by which genetic information from RNA gets transcribed into new DNA. The family of enzymes involved in this process is called  Reverse Transcriptase .


RNA replication is the copying of one RNA to another. Many viruses replicate this way. The enzymes that copy RNA to new RNA, called  RNA-dependent RNA polymerases , are also found in many eukaryotes where they are involved in  RNA silencing . [ 11 ]


RNA editing , in which an RNA sequence is altered by a complex of proteins and a "guide RNA", could also be seen as an RNA-to-RNA transfer.


The central dogma of molecular biology states that once sequential information has passed from nucleic acid to protein it cannot flow back from protein to nucleic acid. Some people believe that the following activities conflict with the central dogma.


After protein amino acid sequences have been translated from nucleic acid chains, they can be edited by appropriate enzymes. This is a form of protein affecting protein sequence not protein transferring information to nucleic acid.


Some proteins are synthesized by  nonribosomal peptide synthetases , which can be big protein complexes, each specializing in synthesizing only one type of peptide. Nonribosomal peptides often have  cyclic  and/or branched structures and can contain non- proteinogenic   amino acids  - both of these factors differentiate them from ribosome synthesized proteins. An example of nonribosomal peptides are some of the antibiotics.


An intein is a "parasitic" segment of a protein that is able to excise itself from the chain of amino acids as they emerge from the ribosome and rejoin the remaining portions with a peptide bond in such a manner that the main protein "backbone" does not fall apart. This is a case of a protein changing its own primary sequence from the sequence originally encoded by the DNA of a gene. Additionally, most inteins contain a  homing endonuclease  or HEG domain which is capable of finding a copy of the parent gene that does not include the intein nucleotide sequence. On contact with the intein-free copy, the HEG domain initiates the  DNA double-stranded break repair  mechanism. This process causes the intein sequence to be copied from the original source gene to the intein-free gene. This is an example of protein directly editing DNA sequence, as well as increasing the sequence's heritable propagation.


Prions  are proteins of particular amino acid sequences in particular conformations. They propagate themselves in host cells by making  conformational changes  in other molecules of protein with the same amino acid sequence, but with a different conformation that is functionally important or detrimental to the organism. Once the protein has been transconformed to the prion folding it changes function. In turn it can convey information into new cells and reconfigure more functional molecules of that sequence into the alternate prion form. In some types of prion in  fungi  this change is continuous and direct; the information flow is Protein → Protein.


Some scientists such as  Alain E. Bussard  and  Eugene Koonin  have argued that prion-mediated inheritance violates the central dogma of molecular biology. [ 12 ] [ 13 ]  However,  Rosalind Ridley  in  Molecular Pathology of the Prions  (2001) has written that "The prion hypothesis is not heretical to the central dogma of molecular biology—that the information necessary to manufacture proteins is encoded in the nucleotide sequence of nucleic acid—because it does not claim that proteins replicate. Rather, it claims that there is a source of information within protein molecules that contributes to their biological function, and that this information can be passed on to other molecules." [ 14 ]


In his  autobiography ,  What Mad Pursuit , Crick wrote about his choice of the word  dogma  and some of the problems it caused him:


"I called this idea the central dogma, for two reasons, I suspect. I had already used the obvious word  hypothesis  in the  sequence hypothesis , and in addition I wanted to suggest that this new assumption was more central and more powerful. ... As it turned out, the use of the word dogma caused almost more trouble than it was worth. Many years later  Jacques Monod  pointed out to me that I did not appear to understand the correct use of the word dogma, which is a belief  that cannot be doubted . I did apprehend this in a vague sort of way but since I thought that  all  religious beliefs were without foundation, I used the word the way I myself thought about it, not as most of the world does, and simply applied it to a grand hypothesis that, however plausible, had little direct experimental support."


Similarly,  Horace Freeland Judson  records in  The Eighth Day of Creation : [ 15 ]


"My mind was, that a dogma was an idea for which there was  no reasonable evidence . You see?!" And Crick gave a roar of delight. "I just didn't  know  what dogma  meant . And I could just as well have called it the 'Central Hypothesis,' or — you know. Which is what I meant to say. Dogma was just a catch phrase."


The  Weismann barrier , proposed by  August Weismann  in 1892, distinguishes between the "immortal" germ cell lineages (the  germ plasm ) which produce gametes and the "disposable" somatic cells. Hereditary information moves only from  germline  cells to  somatic cells  (that is, somatic mutations are not inherited). This, before the discovery of the role or structure of DNA, does not predict the central dogma, but does anticipate its gene-centric view of life, albeit in non-molecular terms. [ 16 ] [ 17 ]


"The Correlation between Relatives on the Supposition of Mendelian Inheritance" [ 1 ]  is a  scientific  paper by  Ronald Fisher  which was published in the  Transactions of the  Royal Society of Edinburgh  in 1918, (volume 52, pages 399–433).


In it, Fisher puts forward the " infinitesimal model ", a  genetics   conceptual model  showing that continuous variation amongst  phenotypic traits  could be the result of  Mendelian inheritance . The paper also contains the first use of the  statistical  term  variance . [ 2 ]  It is considered the foundation of  quantitative genetics . [ 3 ]


Mendelian inheritance  was rediscovered in 1900.  However, there were differences of opinion as to the variation that  natural selection  acted upon.  The  biometric  school, led by  Karl Pearson  followed  Charles Darwin 's idea that small differences were important for  evolution .  The Mendelian school, led by  William Bateson , however thought that  Gregor Mendel 's work gave an evolutionary mechanism with large differences. Joan Box, Fisher's biographer and daughter states in her 1978 book,  The Life of a Scientist [ 4 ]  that Fisher, then a student, had resolved this problem in 1911.


Fisher had originally submitted his paper (then entitled "The correlation to be expected between relatives on the supposition of Mendelian inheritance") to the  Royal Society of London , to be published in their Transactions.  The two referees, the biologist  R. C. Punnett  and the statistician  Karl Pearson , believed that the paper contained areas they were unable to judge, due to lack of expertise, and expressed some reservations. Though the paper was not rejected, Fisher carried on a feud with Pearson from 1917 onwards, and instead sent the paper via  J. Arthur Thomson  to the  Royal Society of Edinburgh , which published it in its  Transactions .


Fisher defined his new term  variance , as the square of the  standard deviation , because of the manner in which variances of  independent   random variables  may be added. He noted the continuous variation in  human  characters.


James Michael Creeth  (3 October 1924 – 15 January 2010) was an  English   biochemist  whose experiments on  DNA   viscosity  confirming the existence of  hydrogen bonds  between the  purine  and  pyrimidine   bases  of DNA were crucial to  Watson  and  Crick 's discovery of the  double helix  structure of DNA.


Creeth was educated at  Northampton Town and County Grammar School , and went on to read  Chemistry  at  University College Nottingham , [ 1 ]
 [ 2 ]  first as a war-time undergraduate (1942–44) and then as a postgraduate PhD student (1944-7) under the supervision of D. O. Jordan and  John Masson Gulland .


The research conducted by Creeth for his PhD  [ 3 ]  and more especially an associated paper  [ 4 ]  in 1947 was one key element amongst others which paved the way to the decoding of the complexities of DNA in 1953. [ 5 ]  Put simply, Creeth and his Nottingham colleagues conducted chemical experiments which demonstrated the hydrogen pair bonding in the molecule.  In his PhD thesis he additionally postulated and sketched a molecular structure for DNA based on hydrogen bonds linking overlapped shorter chains together to form a longer, almost double, chain. In Creeth’s model the hydrogen bonded bases are on the inside of the molecule, which has a phosphate sugar backbone, but there is no helical structure as the X-Ray data was not yet available to provide the data to imply the double helix formation later discerned by Crick and Watson. [ 6 ]


Given it was such a critical discovery, the Nottingham team and Creeth’s role in it have sometimes lacked recognition. [ 7 ]  In the original version of  The Double Helix  Watson admitted to initially having dismissed their work incorrectly only to find that "...a rereading of J. M. Gulland's and D. O. Jordan's papers...made me finally realize the strength of their conclusion that a large fraction, if not all, of the bases formed hydrogen bonds to other bases”. [ 8 ]  Once Watson had recognised the key role of the hydrogen bonds then the correct solution to the decoding of DNA seems to have occurred to him within about a week or ten days. [ 9 ]  Creeth’s personal achievement in conducting such a crucial experiment at age 23 similarly lacked recognition in his lifetime, although his role was posthumously recognised in the expanded  Annotated and Illustrated Double Helix  (2012), [ 10 ]  and also by commemorative events at the  University of Nottingham .


There has been some speculation as to whether the Nottingham team could have gone on to make the breakthrough on decoding DNA if events had turned out differently following the high point of their research in 1947. [ 11 ]  However Creeth left to work in London after completing his PhD, and then Gulland was killed in the  Goswick rail crash  near Berwick on Tweed on 26 October 1947. Some of the necessary scientific processes and knowledge were not in place in 1947, [ 12 ]  but Creeth also later said that he had not guessed just how close the Nottingham team was to the DNA discovery.


Creeth might have moved on to Cambridge University in the early 1950s when he applied for a post-doctoral place there. Had he gone there, he would have arrived a little prior to Watson and Crick with a wealth of knowledge in their chosen field. It is a rather ironic reflection on prevailing academic elitism, that at the time Cambridge only recognised a handful of other universities’ doctorates and these did not include Nottingham: so Creeth was only offered the chance to do a second PhD, an offer which he politely declined. Instead he was proud to win a  Rockefeller Foundation  Fellowship to do postdoctoral work in Wisconsin in the USA. [ 13 ]


Creeth’s later career as a scientist at institutions on three continents focussed largely on proteins. He was an expert in the use and theory of the  analytical ultracentrifuge , in characterising the solution properties of proteins, in particular their size, shape and interactions. He became a leading authority on ‘nature’s natural lubricant -  mucus ’, [ 14 ]  which contains the  glycoproteins  which he studied, and helped to advance knowledge of the role they play in medical conditions such as cystic fibrosis, chronic bronchitis and asthma. He even managed to write a retrospective paper on the development of the analytical centrifuge shortly before his death aged eighty five. [ 15 ]


Martin Henry Dawson  (6 August 1896 – 27 April 1945) was a  Canadian  researcher who made important contributions in the fields of infectious diseases. [ 1 ]


Dawson was born in  Truro, Nova Scotia , a grandson of  John Barnhill Dickie  and educated at  Dalhousie University  and  McGill University . [ 1 ]  His research included studies on the  transformation  of  pneumococci  and on the biological variants of the  streptococcus  and other  microorganisms . Dawson's studies on the nature and treatment of  arthritis  made him a recognized authority in this disorder.  He was a pioneer in  penicillin  therapy, and was the first in the world to prepare it and use it in human disease. This included the successful treatment of bacterial  endocarditis  with penicillin, and the use of gold salts in the treatment of rheumatoid arthritis.


Dawson became the first person in history to administer an antibiotic (penicillin) to a patient, on October 16, 1940. [ 2 ] [ 3 ]


After he had graduated Dalhousie University in Halifax with a  BA  in 1916 he started serving in the Canadian forces in the  First World War . Pte. M. Henry Dawson was with No. 7 Stationary Hospital at La Harve,  France .  He became a Capt. in the Nova Scotia Reg’t of  Canadian Army  Medical Corps. He was wounded in 1917 and again in 1918 and was awarded the  Military Cross  in 1917.


Following the war Dawson attended McGill University in Quebec and received his  M.D.  degree in 1923. After graduating in  Medicine  he worked at the  Royal Victoria Hospital  in  Montreal . In 1926 he was appointed a National Research  Fellow , assigned to the  Rockefeller Institute  in New York.


As a National Research Council fellow he worked with  Oswald Avery  at the Rockefeller Institute. Over Avery's strong objections, Dawson recreated Fred Griffith's discovery that a soluble substance from dead bacteria of one type can effect a repeatable and inheritable change in bacteria of another type [ 4 ]  – a process Dawson termed  transformation  in his six articles on the subject – in which he was the first person in history to put the substance to work in a test tube and even to partially extract it. [ citation needed ]  The phrase stuck and eventually Avery along with  Colin Munro MacLeod  proved the substance was in fact  DNA .


In 1929 Dawson became associated with the Presbyterian Hospital and the Department of Medicine at  Columbia University .


In 1942 Dawson became the victim of  myasthenia gravis , a chronic progressively disabling disease. He died in 1945 at Columbia University Medical Center. [ 1 ]


Hugo Marie de Vries  ( Dutch:   [ˈɦyɣoː   də   ˈvris] ; 16 February 1848 – 21 May 1935) [ 2 ]  was a Dutch  botanist  and one of the first  geneticists . He is known chiefly for suggesting the concept of  genes , rediscovering the laws of heredity in the 1890s while apparently unaware of  Gregor Mendel 's work, for introducing the term " mutation ", and for developing a  mutation theory  of evolution.


De Vries was born in 1848, the eldest son of  Gerrit de Vries  (1818–1900), a lawyer and deacon in the Mennonite congregation in Haarlem and later Prime Minister of the Netherlands from 1872 until 1874, [ 3 ]  and Maria Everardina Reuvens (1823–1914), daughter of a professor in archaeology at  Leiden University . His father became a member of the  Dutch Council of State  in 1862 and moved his family over to  The Hague . From an early age Hugo showed much interest in botany, winning several prizes for his  herbariums  while attending  gymnasium  in Haarlem and The Hague.


In 1866 he enrolled at the Leiden University to major in botany. He enthusiastically took part in  W.F.R. Suringar's  classes and excursions, but was mostly drawn to the experimental botany outlined in  Julius von Sachs ' 'Lehrbuch der Botanik' from 1868. He was also deeply impressed by  Charles Darwin 's evolution theory, despite Suringar's skepticism. He wrote a dissertation on the effect of heat on plant roots, including several statements by Darwin to provoke his professor, and graduated in 1870.


After a short period of teaching, de Vries left in September 1870 to take classes in chemistry and physics at the  Heidelberg University  and work in the laboratory of  Wilhelm Hofmeister . In the second semester of that school year he joined the lab of the esteemed Julius Sachs in  Würzburg  to study plant growth. From September 1871 until 1875 he taught botany, zoology, and geology at schools in  Amsterdam . During each vacation he returned to the lab in Heidelberg to continue his research.


In 1875, the Prussian Ministry of Agriculture offered de Vries a position as professor at the still to be constructed  Landwirtschaftliche Hochschule  ("Royal Agricultural College") in  Berlin . In anticipation, he moved back to Würzburg, where he studied agricultural crops and collaborated with Sachs. By 1877, Berlin's College was still only a plan, and he briefly took up a position teaching at the  University of Halle-Wittenberg . The same year he was offered a position as lecturer in plant physiology at the newly founded  University of Amsterdam . He was made adjunct professor in 1878 and full professor on his birthday in 1881, partly to keep him from moving to the Berlin College, which finally opened that year.
De Vries was also professor and director of Amsterdam's Botanical Institute and  Garden  from 1885 to 1918.


In 1889, de Vries published his book  Intracellular Pangenesis , [ 4 ]  in which, based on a modified version of  Charles Darwin 's theory of  Pangenesis  of 1868, he postulated that different characters have different hereditary carriers. He specifically postulated that inheritance of specific traits in organisms comes in particles. He called these units  pangenes , a term 20 years later to be shortened to  genes  by  Wilhelm Johannsen .


To support his theory of pangenes, which was not widely noticed at the time, de Vries conducted a series of experiments hybridising varieties of multiple plant species in the 1890s. Unaware of Mendel's work, de Vries used the laws of  dominance and recessiveness ,  segregation , and  independent assortment  to explain the 3:1 ratio of  phenotypes  in the second generation. [ 5 ]  His observations also confirmed his hypothesis that inheritance of specific traits in organisms comes in particles.


He further speculated that genes could cross the species barrier, with the same gene being responsible for hairiness in two different species of flower. Although generally true in a sense ( orthologous genes , inherited from a common ancestor of both species, tend to stay responsible for similar phenotypes), de Vries meant a physical cross between species. This actually also happens, though very rarely in higher organisms (see  horizontal gene transfer ). De Vries' work on genetics inspired the research of  Jantina Tammes , who worked with him for a period in 1898.


In the late 1890s, de Vries became aware of Mendel's obscure paper of thirty years earlier and he altered some of his terminology to match. When he published the results of his experiments in the French journal  Comptes rendus de l'Académie des Sciences  in 1900, he neglected to mention Mendel's work, but after criticism by  Carl Correns  he conceded Mendel's priority.


Correns and  Erich von Tschermak  now share credit for the rediscovery of Mendel's laws. Correns was a student of  Nägeli , a renowned botanist with whom Mendel corresponded about his work with peas but who failed to understand its significance, while, coincidentally, Tschermak's grandfather taught Mendel botany during his student days in Vienna.


In his own time, de Vries was best known for his  mutation theory . In 1886, he had discovered new forms among a group of  Oenothera lamarckiana , a species of evening primrose, growing wild in an abandoned potato field near Hilversum, having escaped a nearby garden. [ 6 ]  Taking seeds from these, he found that they produced many new varieties in his experimental gardens; he introduced the term  mutations  for these suddenly appearing variations. In his two-volume publication  The Mutation Theory  (1900–1903) he postulated that evolution, especially the origin of species, might occur more frequently with such large-scale changes than via Darwinian gradualism, basically suggesting a form of  saltationism . De Vries's theory was one of the chief contenders for the explanation of how evolution worked, leading, for example,  Thomas Hunt Morgan  to study mutations in the fruit fly, until the  modern evolutionary synthesis  became the dominant model in the 1930s. During the early decades of the twentieth century, de Vries' theory was enormously influential and continued to fascinate non-biologists long after the scientific community had abandoned much of it [ 7 ]  (while retaining the idea of mutations as a crucial source of natural variation). The large-scale primrose variations turned out to be the result of various chromosomal abnormalities, including  ring chromosomes ,  balanced lethals  and chromosome duplications ( polyploidy ), while the term mutation now generally is restricted to discrete changes in the DNA sequence. However, the popular understanding of "mutation" as a sudden leap to a new species has remained a staple theme of science fiction, e.g. the  X-Men movies  (and the comic books that preceded them). [ 8 ]


In a published lecture of 1903 ( Befruchtung und Bastardierung , Veit, Leipzig), De Vries was also the first to suggest the occurrence of recombinations between  homologous chromosomes , now known as  chromosomal crossovers , within a year after chromosomes were implicated in Mendelian inheritance by  Walter Sutton . [ 9 ]


Botanist  Daniel Trembly MacDougal  attended his lectures in United States on Mutation Theory. In 1905 he helped published these lectures into a book  Species and Varieties: Their Origin by Mutation. [ 10 ] [ 11 ]


In 1878 de Vries became member of the  Royal Netherlands Academy of Arts and Sciences . [ 12 ]  He was elected to the  American Philosophical Society  in 1903 and the United States  National Academy of Sciences  in 1904. [ 13 ] [ 14 ]  In May 1905, de Vries was elected  Foreign Member of the Royal Society . In 1910, he was elected a member of the  Royal Swedish Academy of Sciences . In 1921, he was elected to the  American Academy of Arts and Sciences . [ 15 ]  He was awarded the  Darwin Medal  in 1906 and the  Linnean Medal  in 1929.


He retired in 1918 from the University of Amsterdam and withdrew to his estate De Boeckhorst in  Lunteren  where he had large experimental gardens. He continued his studies with new forms until his death in 1935.


His best known works are:


Max Ludwig Henning Delbrück  ( German:   [maks   ˈdɛl.bʁʏk]   ⓘ ; September 4, 1906 – March 9, 1981) was a  German–American   biophysicist  who participated in launching the  molecular biology   research program  in the late 1930s.  He stimulated  physical scientists ' interest into  biology , especially as to  basic research  to physically explain  genes , mysterious at the time.  Formed in 1945 and led by Delbrück along with  Salvador Luria  and  Alfred Hershey , the  Phage Group  made substantial headway unraveling important aspects of  genetics . The three shared the 1969  Nobel Prize in Physiology or Medicine  "for their discoveries concerning the replication mechanism and the genetic structure of viruses". [ 3 ]  He was the first physicist to predict what is now called  Delbrück scattering . [ 4 ] [ 5 ] [ 6 ]


Delbrück was born in  Berlin ,  German Empire . His mother was granddaughter of  Justus von Liebig , an eminent  chemist , while his father  Hans Delbrück  was a  history  professor at the  University of Berlin . In 1937, Delbrück left Nazi Germany for America—first California, then Tennessee—becoming a  US citizen  in 1945. [ 1 ]  In 1941, he married Mary Bruce. They had four children.


Delbrück's brother Justus, a lawyer, as well as his sister  Emmi Bonhoeffer  were active along with his brothers-in-law  Klaus Bonhoeffer  and  Dietrich Bonhoeffer  in  resistance to Nazism . Found guilty by the  People's Court  for roles in the  July 20, 1944 plot to assassinate Hitler , Dietrich and Klaus were executed in 1945 by the  RSHA . Justus died in Soviet custody that same year. His son, Tobias Delbruck is a professor at the Institute of Neuroinformatics at the University of Zurich and ETH Zurich. [ 7 ]  Professor Tobias Delbruck is also one of the pioneers in the domain of event cameras, [ 8 ]  now increasingly being deployed in dynamic vision systems.


Delbrück studied  astrophysics , shifting towards  theoretical physics , at the  University of Göttingen . After completing his  Ph.D.  there in 1930, [ 9 ]  he traveled through  England ,  Denmark , and  Switzerland . He met  Wolfgang Pauli  and  Niels Bohr , who interested him in  biology .


Delbrück returned to Berlin in 1932 as an assistant to  Lise Meitner , who was collaborating with  Otto Hahn  on irradiation of  uranium  with  neutrons .  Delbrück wrote a few papers, including one in 1933 on  gamma rays ' scattering by a  Coulomb  field's polarization of a vacuum.  Though theoretically tenable, his conclusion was misplaced, whereas  Hans Bethe  some 20 years later confirmed the phenomenon and named it " Delbrück scattering ". [ 10 ]


In 1935, Delbrück published a collaboration with  Nikolay Timofeev-Ressovsky  and  Karl Zimmer  the major work,  Über die Natur der Genmutation und der Genstruktur . It was considered to be a major advance in understanding the nature of gene mutation and gene structure. [ 11 ]  The work was a keystone in the formation of molecular genetics. [ 12 ]  It was also an inspirational starting point for   Erwin Schrödinger's  thinking, a course of lectures in 1943,  and the eventual writing of the book  What Is Life? The Physical Aspect of the Living Cell . [ 13 ]


In 1937, he attained a fellowship from  Rockefeller Foundation —which was launching the  molecular biology   research program —to research  genetics  of the fruit fly,  Drosophila melanogaster , in  California Institute of Technology 's biology department, [ 14 ]  where Delbrück could blend interests in biochemistry and genetics. [ 15 ]   While at  Caltech , Delbrück researched  bacteria  and their viruses ( bacteriophages  or  phages ). In 1939, with  Emory L. Ellis , [ 16 ] [ 17 ]  he coauthored "The growth of bacteriophage",  a paper reporting that the  viruses  reproduce in  one step , not exponentially as do  cellular  organisms.


Although Delbrück's  Rockefeller Foundation  fellowship expired in 1939, the Foundation matched him up with  Vanderbilt University  in  Nashville, Tennessee , where from 1940 to 1947 he taught  physics , yet had his laboratory in the biology department. [ 19 ]   In 1941, Delbrück met  Salvador Luria  of  Indiana University  who began visiting Vanderbilt. [ 19 ]   In 1942,  Delbrück and Luria published  on  bacterial  resistance to  virus  infection mediated by random  mutation . [ 19 ]   Alfred Hershey  of  Washington University in St. Louis  began visiting in 1943. [ 19 ]  The Luria–Delbrück experiment, also called the Fluctuation Test, demonstrated that Darwin's theory of natural selection acting on random mutations applies to bacteria as well as to more complex organisms. The 1969 Nobel Prize in Physiology or Medicine was awarded to both scientists in part for this work. To put this work in its historical perspective, Lamarck in 1801 first presented his theory of Inheritance of Acquired Characteristics, which stated that if an organism changes during life in order to adapt to its environment (for example stretches its neck to reach for tall trees), those changes are passed on to its offspring. He also said that evolution happens according to a predetermined plan. Darwin published his theory of evolution in his 1859 book On the Origin of Species with compelling evidence contradicting Lamarck. Darwin said that evolution is not predetermined but that there are inherent variations in all organisms, and that those variations that confer increased fitness are selected by the environment and passed on to the offspring. In the feud between Lamarck and Darwin, Darwin talked of pre-existing changes, but the nature of these changes was not known and had to await the science of genetics by Gregor Mendel's experiments on pea plants published in 1866. Support for Darwin's theory was provided when Thomas Hunt Morgan discovered that a mutated white-eyed fruit fly among red-eyed flies was able to reproduce true white-eyed offspring. The most elegant and convincing support for Darwin's ideas, however, was provided by the Luria-Delbruck experiment, [ 20 ] [ 21 ] [ 22 ]  which showed that mutations conferring resistance of the bacterium E. coli to T1 bacteriophage (virus) existed in the population prior to exposure to T1 and were not induced by adding T1. In other words, mutations are random events that occur whether or not they prove to be useful, while selection (for T1 resistance upon challenge with T1 in this case) provides the direction in evolution by retaining those mutations that are advantageous, discarding those that are harmful (T1 sensitivity in this case). This experiment dealt a blow to Lamarckian inheritance and set the stage for tremendous advances in genetics and molecular biology, launching a tsunami of research that eventually led to the discovery of DNA as the hereditary material and to cracking the genetic code.  Of course, by then Avery, along with McCloud (and earlier, McCarty) was well on the way to showing the genetic capability of DNA.


In 1945, Delbrück, Luria, and Hershey set up a course in  bacteriophage  genetics at  Cold Spring Harbor Laboratory  on  Long Island, New York . [ 19 ]   This  Phage Group  spurred  molecular biology 's early development. [ 23 ]   Delbrück received the 1969  Nobel Prize in Physiology or Medicine , shared with Luria and Hershey "for their discoveries concerning the replication mechanism and the genetic structure of viruses". [ 3 ] [ 19 ] [ 24 ]  The committee also noted that "The honour in the first place goes to Delbrück who transformed bacteriophage research from vague empiricism to an exact science. He analyzed and defined the conditions for precise measurement of the biological effects. Together with Luria he elaborated the quantitative methods and established the statistical criteria for evaluation which made the subsequent penetrating studies possible. Delbrück's and Luria's forte is perhaps mainly theoretical analysis, whereas Hershey above all is an eminently skillful experimenter. The three of them supplement each other well also in these respects." That year, Delbrück and  Luria  were also awarded by  Columbia University  the  Louisa Gross Horwitz Prize .  In late 1947, as Vanderbilt lacked the resources to keep him, Delbrück had returned to Caltech as a professor of biology, and remained there for the rest of his career. [ 19 ]   Meanwhile, he set up  University of Cologne 's institute for  molecular genetics .


In addition to the Nobel Prize, Delbrück was elected a  Foreign Member of the Royal Society (ForMemRS) in 1967 . [ 25 ]  He was elected an  EMBO Member  in 1970. [ 26 ]  The  Max Delbruck Prize , formerly known as the biological physics prize, is awarded by the  American Physical Society  and named in his honour. The  Max Delbrück Center , in Berlin, Germany, national research center for molecular medicine of the  Helmholtz Association  also bears his name.


Delbrück helped spur  physical scientists ' interest in biology.  His inferences on genes' susceptibility to mutation was relied on by physicist  Erwin Schrödinger  in his 1944 book  What Is Life? , [ 27 ]  which conjectured genes were an "aperiodic crystal" storing codescript and influenced crystallographer  Rosalind Franklin  and biologists  Francis Crick  and  James D. Watson  in their 1953 identification of cellular DNA's molecular structure as a double helix. [ 28 ] [ 29 ]  In 1977, he retired from  Caltech , remaining a Professor of Biology emeritus. He became interested in the behavioral sciences and spent some unfruitful effort on mold behavior in the 1960s.


Max Delbrück died, at age 74, on the evening of Monday, March 9, 1981, at  Huntington Memorial Hospital  in  Pasadena, California .  On August 26 to 27, 2006—the year Delbrück would have turned 100—family and friends gathered at Cold Spring Harbor Laboratory to reminisce on his life and work. [ 30 ]   Although Delbrück held some anti- reductionist  views; he conjectured that ultimately a paradox—akin perhaps to the  waveparticle duality  of  physics —would be revealed about life. His view however, was later refuted upon the discovery of the  double helix structure of DNA . [ 31 ]


DNA profiling  (also called  DNA fingerprinting  and  genetic fingerprinting ) is the process of determining an individual's deoxyribonucleic acid ( DNA ) characteristics. DNA analysis intended to identify a species, rather than an individual, is called  DNA barcoding .


DNA profiling is a  forensic  technique in  criminal investigations , comparing criminal suspects' profiles to DNA evidence so as to assess the likelihood of their involvement in the crime. [ 1 ] [ 2 ]  It is also used in  paternity testing , [ 3 ]  to establish immigration eligibility, [ 4 ]  and in  genealogical  and medical research. DNA profiling has also been used in the study of animal and plant populations in the fields of zoology, botany, and agriculture. [ 5 ]


Starting in the mid 1970s, scientific advances allowed the use of DNA as a material for the identification of an individual. The first patent covering the direct use of DNA variation for forensics ( US5593832A [ 6 ] [ 7 ] ) was filed by  Jeffrey Glassberg  in 1983, based upon work he had done while at  Rockefeller University  in the United States in 1981.


British  geneticist Sir  Alec Jeffreys  independently developed a process for DNA profiling in 1984 while working in the Department of Genetics at the  University of Leicester . Jeffreys discovered that a DNA examiner could establish patterns in unknown DNA. These patterns were a part of inherited traits that could be used to advance the field of relationship analysis. These discoveries led to the first use of DNA profiling in a criminal case. [ 8 ] [ 9 ] [ 10 ] [ 11 ]


The process, developed by Jeffreys in conjunction with Peter Gill and Dave Werrett of the  Forensic Science Service  (FSS), was first used forensically in the solving of the murder of two teenagers who had been raped and murdered in  Narborough, Leicestershire  in 1983 and 1986. In the murder inquiry, led by Detective David Baker, the DNA contained within blood samples obtained voluntarily from around 5,000 local men who willingly assisted  Leicestershire Constabulary  with the investigation, resulted in the exoneration of Richard Buckland, an initial suspect who had confessed to one of the crimes, and the subsequent conviction of  Colin Pitchfork  on January 2, 1988. Pitchfork, a local bakery employee, had coerced his coworker Ian Kelly to stand in for him when providing a blood sample—Kelly then used a forged passport to impersonate Pitchfork. Another coworker reported the deception to the police. Pitchfork was arrested, and his blood was sent to Jeffreys' lab for processing and profile development. Pitchfork's profile matched that of DNA left by the murderer which confirmed Pitchfork's presence at both crime scenes; he pleaded guilty to both murders. [ 12 ]  After some years, a chemical company named  Imperial Chemical Industries  (ICI) introduced the first ever commercially available kit to the world. Despite being a relatively recent field, it had a significant global influence on both criminal justice system and society. [ 13 ]


Although 99.9% of human DNA sequences are the same in every person, enough of the DNA is different that it is possible to distinguish one individual from another, unless they are  monozygotic (identical) twins . [ 14 ]  DNA profiling uses repetitive sequences that are highly variable, [ 14 ]  called  variable number tandem repeats  (VNTRs), in particular short tandem repeats (STRs), also known as  microsatellites , and  minisatellites . VNTR  loci  are similar between closely related individuals, but are so variable that unrelated individuals are unlikely to have the same VNTRs.


Before VNTRs and STRs, people like Jeffreys used a process called  restriction fragment length polymorphism (RFLP) . This process regularly used large portions of DNA to analyze the differences between two DNA samples. RFLP was among the first technologies used in DNA profiling and analysis. However, as technology has evolved, new technologies, like STR, emerged and took the place of older technology like RFLP. [ 15 ]


The admissibility of DNA evidence in courts was disputed in the United States in the 1980s and 1990s, but has since become more universally accepted due to improved techniques. [ 16 ]


When a sample such as  blood  or  saliva  is obtained, the DNA is only a small part of what is present in the sample. Before the DNA can be analyzed, it must be  extracted  from the cells and purified. There are many ways this can be accomplished, but all methods follow the same basic procedure. The cell and nuclear membranes need to be broken up to allow the DNA to be free in solution. Once the DNA is free, it can be separated from all other cellular components. After the DNA has been separated in solution, the remaining cellular debris can then be removed from the solution and discarded, leaving only DNA. The most common methods of DNA extraction include  organic extraction  (also called  phenol–chloroform extraction ), [ 17 ]   Chelex extraction , and  solid-phase extraction .  Differential extraction  is a modified version of extraction in which DNA from two different types of cells can be separated from each other before being purified from the solution. Each method of extraction works well in the laboratory, but analysts typically select their preferred method based on factors such as the cost, the time involved, the quantity of DNA yielded, and the quality of DNA yielded. [ 18 ]


RFLP stands for restriction fragment length polymorphism and, in terms of DNA analysis, describes a DNA testing method which utilizes restriction  enzymes  to "cut" the DNA at short and specific sequences throughout the sample. To start off processing in the laboratory, the sample has to first go through an extraction protocol, which may vary depending on the sample type or laboratory SOPs (Standard Operating Procedures). Once the DNA has been "extracted" from the cells within the sample and separated away from extraneous cellular materials and any nucleases that would degrade the DNA, the sample can then be introduced to the desired restriction enzymes to be cut up into discernable fragments. Following the enzyme digestion, a Southern Blot is performed.  Southern Blots  are a size-based separation method that are performed on a gel with either radioactive or chemiluminescent probes. RFLP could be conducted with single-locus or multi-locus probes (probes which target either one location on the DNA or multiple locations on the DNA). Incorporating the multi-locus probes allowed for higher discrimination power for the analysis, however completion of this process could take several days to a week for one sample due to the extreme amount of time required by each step required for visualization of the probes.


This technique was developed in 1983 by Kary Mullis. PCR is now a common and important technique used in medical and biological research labs for a variety of applications. [ 19 ]


PCR, or Polymerase Chain Reaction, is a widely used molecular biology technique to amplify a specific DNA sequence.


Amplification is achieved by a series of three steps:


1- Denaturation  : In this step, the DNA is heated to 95  °C  to dissociate the hydrogen bonds between the complementary base pairs of the double-stranded DNA.


2-Annealing  : During this stage the reaction is cooled to 50-65  °C  . This enables the primers to attach to a specific location on the single -stranded template DNA by way of hydrogen bonding.


3-Extension  : A thermostable DNA polymerase which is Taq polymerase is commonly used at this step. This is done at a temperature of 72  °C  . DNA polymerase adds nucleotides in the 5'-3' direction and synthesizes the complementary strand of the DNA template .


The system of DNA profiling used today is based on  polymerase chain reaction  (PCR) and uses simple sequences. [ 9 ]


From country to country, different STR-based DNA-profiling systems are in use. In North America, systems that amplify the  CODIS  20 [ 21 ]  core loci are almost universal, whereas in the United Kingdom the  DNA-17  loci system is in use, and Australia uses 18 core markers. [ 22 ]


The true power of  STR analysis  is in its statistical power of discrimination. Because the 20 loci that are currently used for discrimination in CODIS are  independently assorted  (having a certain number of repeats at one locus does not change the likelihood of having any number of repeats at any other locus), the  product rule for probabilities  can be applied. This means that, if someone has the DNA type of ABC, where the three loci were independent, then the probability of that individual having that DNA type is the probability of having type A times the probability of having type B times the probability of having type C. This has resulted in the ability to generate match probabilities of 1 in a quintillion (1x10 18 ) or more. [ further explanation needed ]  However, DNA database searches showed much more frequent than expected false DNA profile matches. [ 23 ]


Due to the paternal inheritance, Y-haplotypes provide information about the genetic ancestry of the male population. To investigate this population history, and to provide estimates for haplotype frequencies in criminal casework, the "Y haplotype reference database (YHRD)" has been created in 2000 as an online resource. It currently comprises more than 300,000 minimal (8 locus) haplotypes from world-wide populations. [ 24 ]


mtDNA can be obtained from such material as hair shafts and old bones/teeth. [ 25 ]  Control mechanism based on interaction point with data. This can be determined by tooled placement in sample. [ 26 ]


When people think of DNA analysis, they often think about television shows like  NCIS  or  CSI , which portray DNA samples coming into a lab and being instantly analyzed, followed by the pulling up of a picture of the suspect within minutes. However, the reality is quite different, and perfect DNA samples are often not collected from the scene of a crime. Homicide victims are frequently left exposed to harsh conditions before they are found, and objects that are used to commit crimes have often been handled by more than one person. The two most prevalent issues that forensic scientists encounter when analyzing DNA samples are degraded samples and DNA mixtures. [ 27 ]


Before modern PCR methods existed, it was almost impossible to analyze degraded DNA samples. Methods like restriction fragment length polymorphism (RFLP), which was the first technique used for DNA analysis in forensic science, required high molecular weight DNA in the sample in order to get reliable data. High molecular weight DNA, however, is lacking in degraded samples, as the DNA is too fragmented to carry out RFLP accurately. It was only when polymerase chain reaction techniques were invented that analysis of degraded DNA samples were able to be carried out. Multiplex PCR in particular made it possible to isolate and to amplify the small fragments of DNA that are still left in degraded samples. When multiplex PCR methods are compared to the older methods like RFLP, a vast difference can be seen. Multiplex PCR can theoretically amplify less than 1 ng of DNA, but RFLP had to have a least 100 ng of DNA in order to carry out an analysis. [ 28 ]


Low-template DNA can happen when there is less than 0.1 ng( [ 29 ] ) of DNA in a sample. This can lead to more stochastic effects (random events) such as allelic dropout or allelic drop-in which can alter the interpretation of a DNA profile. These stochastic effects can lead to the unequal amplification of the 2 alleles that come from a heterozygous individual. It is especially important to take low-template DNA into account when dealing with a mixture of DNA sample. This is because for one (or more) of the contributors in the mixture, they are more likely to have less than the optimal amount of DNA for the PCR reaction to work properly. [ 30 ]  Therefore, stochastic thresholds are developed for DNA profile interpretation. The stochastic threshold is the minimum peak height (RFU value), seen in an electropherogram where dropout occurs. If the peak height value is above this threshold, then it is reasonable to assume that allelic dropout has not occurred. For example, if only 1 peak is seen for a particular locus in the electropherogram but its peak height is above the stochastic threshold, then we can reasonably assume that this individual is homozygous and is not missing its heterozygous partner allele that otherwise would have dropped out due to having low-template DNA. Allelic dropout can occur when there is low-template DNA because there is such little DNA to start with that at this locus the contributor to the DNA sample (or mixture) is a true heterozygote but the other allele is not amplified and so it would be lost. Allelic drop-in [ 31 ]  can also occur when there is low-template DNA because sometimes the stutter peak can be amplified. The stutter is an artifact of PCR. During the PCR reaction, DNA Polymerase will come in and add nucleotides off of the primer, but this whole process is very dynamic, meaning that the DNA Polymerase is constantly binding, popping off and then rebinding. Therefore, sometimes DNA Polymerase will rejoin at the short tandem repeat ahead of it, leading to a short tandem repeat that is 1 repeat less than the template. During PCR, if DNA Polymerase happens to bind to a locus in stutter and starts to amplify it to make lots of copies, then this stutter product will appear randomly in the electropherogram, leading to allelic drop-in.


In instances in which DNA samples are degraded, like if there are intense fires or all that remains are bone fragments, standard STR testing on those samples can be inadequate. When standard STR testing is done on highly degraded samples, the larger STR loci often drop out, and only partial DNA profiles are obtained. Partial DNA profiles can be a powerful tool, but the probability of a random match is larger than if a full profile was obtained. One method that has been developed to analyse degraded DNA samples is to use miniSTR technology. In the new approach, primers are specially designed to bind closer to the STR region. [ 32 ]


In normal STR testing, the primers bind to longer sequences that contain the STR region within the segment. MiniSTR analysis, however, targets only the STR location, which results in a DNA product that is much smaller. [ 32 ]


By placing the primers closer to the actual STR regions, there is a higher chance that successful amplification of this region will occur. Successful amplification of those STR regions can now occur, and more complete DNA profiles can be obtained.  The success that smaller PCR products produce a higher success rate with highly degraded samples was first reported in 1995, when miniSTR technology was used to identify victims of the Waco fire. [ 33 ]


Mixtures are another common issue faced by forensic scientists when they are analyzing unknown or questionable DNA samples. A mixture is defined as a DNA sample that contains two or more individual contributors. [ 28 ]  That can often occur when a DNA sample is swabbed from an item that is handled by more than one person or when a sample contains both the victim's and the assailant's DNA. The presence of more than one individual in a DNA sample can make it challenging to detect individual profiles, and interpretation of mixtures should be performed only by highly trained individuals. Mixtures that contain two or three individuals can be interpreted with difficulty. Mixtures that contain four or more individuals are much too convoluted to get individual profiles. One common scenario in which a mixture is often obtained is in the case of sexual assault. A sample may be collected that contains material from the victim, the victim's consensual sexual partners, and the perpetrator(s). [ 34 ]


Mixtures can generally be sorted into three categories: Type A, Type B, and Type C. [ 35 ]  Type A mixtures have alleles with similar peak-heights all around, so the contributors cannot be distinguished from each other. Type B mixtures can be deconvoluted by comparing peak-height ratios to determine which alleles were donated together. Type C mixtures cannot be safely interpreted with current technology because the samples were affected by DNA degradation or having too small a quantity of DNA present.


When looking at an electropherogram, it is possible to determine the number of contributors in less complex mixtures based on the number of peaks located in each locus. In comparison to a single source profile, which will only have one or two peaks at each locus, a mixture is when there are three or more peaks at two or more loci. [ 36 ]  If there are three peaks at only a single locus, then it is possible to have a single contributor who is tri-allelic at that locus. [ 37 ]  Two person mixtures will have between two and four peaks at each locus, and three person mixtures will have between three and six peaks at each locus. Mixtures become increasingly difficult to deconvolute as the number of contributors increases.


As detection methods in DNA profiling advance, forensic scientists are seeing more DNA samples that contain mixtures, as even the smallest contributor can now be detected by modern tests. The ease in which forensic scientists have in interpenetrating DNA mixtures largely depends on the ratio of DNA present from each individual, the genotype combinations, and the total amount of DNA amplified. [ 38 ]  The DNA ratio is often the most important aspect to look at in determining whether a mixture can be interpreted. For example, if a DNA sample had two contributors, it would be easy to interpret individual profiles if the ratio of DNA contributed by one person was much higher than the second person. When a sample has three or more contributors, it becomes extremely difficult to determine individual profiles. Fortunately, advancements in probabilistic genotyping may make that sort of determination possible in the future.  Probabilistic genotyping  uses complex computer software to run through thousands of mathematical computations to produce statistical likelihoods of individual genotypes found in a mixture. [ 39 ]


DNA profiling in plant:


Plant DNA profiling (fingerprinting) is a method for identifying cultivars that uses molecular marker techniques. This method is gaining attention due to Trade Related Intellectual property rights (TRIPs) and the Convention on Biological Diversity (CBD). [ 40 ]


Advantages of Plant DNA profiling:


Identification, authentication, specific distinction, detecting adulteration and identifying phytoconstituents are all possible with DNA fingerprinting in medical plants. [ 41 ]


DNA based markers are critical for these applications, determining the future of scientific study in pharmacognosy. [ 41 ]


It also helps with determining the traits (such as seed size and leaf color) are likely to improve the offspring or not. [ 42 ]


An early application of a  DNA database  was the compilation of a Mitochondrial DNA Concordance, [ 43 ]  prepared by Kevin W. P. Miller and John L. Dawson at the  University of Cambridge  from 1996 to 1999 [ 44 ]  from data collected as part of Miller's PhD thesis. There are now several  DNA databases  in existence around the world. Some are private, but most of the largest databases are government-controlled. The  United States  maintains the largest  DNA database , with the  Combined DNA Index System  (CODIS) holding over 13 million records as of May 2018. [ 45 ]  The  United Kingdom  maintains the  National DNA Database  (NDNAD), which is of similar size, despite the UK's smaller population. The size of this database, and its rate of growth, are giving concern to  civil liberties  groups in the UK, where police have wide-ranging powers to take samples and retain them even in the event of acquittal. [ 46 ]  The Conservative–Liberal Democrat coalition partially addressed these concerns with part 1 of the  Protection of Freedoms Act 2012 , under which DNA samples must be deleted if suspects are acquitted or not charged, except in relation to certain (mostly serious or sexual) offenses. Public discourse around the introduction of advanced forensic techniques (such as genetic genealogy using public genealogy databases and DNA phenotyping approaches) has been limited, disjointed, unfocused, and raises issues of privacy and consent that may warrant the establishment of additional legal protections. [ 47 ]


The  U.S. Patriot Act  of the United States provides a means for the U.S. government to get DNA samples from suspected terrorists. DNA information from crimes is collected and deposited into the  CODIS  database, which is maintained by the  FBI . CODIS enables law enforcement officials to test DNA samples from crimes for matches within the database, providing a means of finding specific biological profiles associated with collected DNA evidence. [ 48 ]


When a match is made from a national DNA databank to link a crime scene to an offender having provided a DNA sample to a database, that link is often referred to as a  cold hit . A cold hit is of value in referring the police agency to a specific suspect but is of less evidential value than a DNA match made from outside the DNA Databank. [ 49 ]


FBI agents cannot legally store DNA of a person not convicted of a crime. DNA collected from a suspect not later convicted must be disposed of and not entered into the database. In 1998, a man residing in the UK was arrested on accusation of burglary. His DNA was taken and tested, and he was later released. Nine months later, this man's DNA was accidentally and illegally entered in the DNA database. New DNA is automatically compared to the DNA found at cold cases and, in this case, this man was found to be a match to DNA found at a rape and assault case one year earlier. The government then prosecuted him for these crimes. During the trial the DNA match was requested to be removed from the evidence because it had been illegally entered into the database. The request was carried out. [ 50 ]
The DNA of the perpetrator, collected from victims of rape, can be stored for years until a match is found. In 2014, to address this problem, Congress extended a bill that helps states deal with "a backlog" of evidence. [ 51 ]


DNA profiling databases in Plants:


PIDS:


PIDS(Plant international DNA-fingerprinting system) is an open source web server and free software based plant international DNA fingerprinting system.


It manages huge amount of microsatellite DNA fingerprint data, performs genetic studies, and automates collection, storage and maintenance while decreasing human error and increasing efficiency.


The system may be tailored to specific laboratory needs, making it a valuable tool for plant breeders, forensic science, and human fingerprint recognition.


It keeps track of experiments, standardizes data and promotes inter-database communication.


It also helps with the regulation of variety quality, the preservation of variety rights and the use of molecular markers in breeding by providing location statistics, merging, comparison and genetic analysis function. [ 52 ]


When using  RFLP , the theoretical risk of a coincidental match is 1 in 100 billion (100,000,000,000) although the practical risk is actually 1 in 1,000 because  monozygotic twins  are 0.2% of the human population. [ 53 ]  Moreover, the rate of laboratory error is almost certainly higher than that and actual laboratory procedures often do not reflect the theory under which the coincidence probabilities were computed. For example, coincidence probabilities may be calculated based on the probabilities that markers in two samples have bands in  precisely  the same location, but a laboratory worker may conclude that similar but not precisely-identical band patterns result from identical genetic samples with some imperfection in the agarose gel. However, in that case, the laboratory worker increases the coincidence risk by expanding the criteria for declaring a match. Studies conducted in the 2000s quoted relatively-high error rates, which may be cause for concern. [ 54 ]  In the early days of genetic fingerprinting, the necessary population data to compute a match probability accurately was sometimes unavailable. Between 1992 and 1996, arbitrary-low ceilings were controversially put on match probabilities used in RFLP analysis, rather than the higher theoretically computed ones. [ 55 ]


It is possible to use DNA profiling as evidence of genetic relationship although such evidence varies in strength from weak to positive. Testing that shows no relationship is absolutely certain. Further, while almost all individuals have a single and distinct set of genes, ultra-rare individuals, known as " chimeras ", have at least two different sets of genes. There have been two cases of DNA profiling that falsely suggested that a mother was unrelated to her children. [ 56 ]


The functional analysis of genes and their coding sequences ( open reading frames  [ORFs]) typically requires that each ORF be expressed, the encoded protein purified, antibodies produced, phenotypes examined, intracellular localization determined, and interactions with other proteins sought. [ 57 ]  In a study conducted by the life science company Nucleix and published in the journal  Forensic Science International , scientists found that an  in vitro  synthesized sample of DNA matching any desired genetic profile can be constructed using standard  molecular biology  techniques without obtaining any actual tissue from that person.


Familial DNA searching (sometimes referred to as "familial DNA" or "familial DNA database searching") is the practice of creating new investigative leads in cases where DNA evidence found at the scene of a crime (forensic profile) strongly resembles that of an existing DNA profile (offender profile) in a state DNA database but there is not an exact match. [ 58 ] [ 59 ]  After all other leads have been exhausted, investigators may use specially developed software to compare the forensic profile to all profiles taken from a state's DNA database to generate a list of those offenders already in the database who are most likely to be a very close relative of the individual whose DNA is in the forensic profile. [ 60 ]


Familial DNA database searching was first used in an investigation leading to the conviction of Jeffrey Gafoor of the  murder of Lynette White  in the United Kingdom on 4 July 2003. DNA evidence was matched to Gafoor's nephew, who at 14 years old had not been born at the time of the murder in 1988. It was used again in 2004 [ 61 ]  to find a man who threw a brick from a motorway bridge and hit a lorry driver, killing him. DNA found on the brick matched that found at the scene of a car theft earlier in the day, but there were no good matches on the national DNA database. A wider search found a partial match to an individual; on being questioned, this man revealed he had a brother, Craig Harman, who lived very close to the original crime scene. Harman voluntarily submitted a DNA sample, and confessed when it matched the sample from the brick. [ 62 ]  As of 2011, familial DNA database searching is not conducted on a national level in the United States, where states determine how and when to conduct familial searches. The first familial DNA search with a subsequent conviction in the United States was conducted in  Denver , Colorado, in 2008, using software developed under the leadership of  Denver District Attorney   Mitch Morrissey  and Denver Police Department Crime Lab Director Gregg LaBerge. [ 63 ]  California was the first state to implement a policy for familial searching under then-Attorney General  Jerry Brown , who later became Governor. [ 64 ]  In his role as consultant to the Familial Search Working Group of the  California Department of Justice , former  Alameda County  Prosecutor Rock Harmon is widely considered to have been the catalyst in the adoption of familial search technology in California. The technique was used to catch the Los Angeles serial killer known as the " Grim Sleeper " in 2010. [ 65 ]  It was not a witness or informant that tipped off law enforcement to the identity of the "Grim Sleeper" serial killer, who had eluded police for more than two decades, but DNA from the suspect's own son. The suspect's son had been arrested and convicted in a felony weapons charge and swabbed for DNA the year before. When his DNA was entered into the database of convicted felons, detectives were alerted to a partial match to evidence found at the "Grim Sleeper" crime scenes. David Franklin Jr., also known as the Grim Sleeper, was charged with ten counts of murder and one count of attempted murder. [ 66 ]  More recently, familial DNA led to the arrest of 21-year-old Elvis Garcia on charges of sexual assault and false imprisonment of a woman in  Santa Cruz  in 2008. [ 67 ]  In March 2011  Virginia  Governor  Bob McDonnell  announced that Virginia would begin using familial DNA searches. [ 68 ]


At a press conference in Virginia on 7 March 2011, regarding the  East Coast Rapist , Prince William County prosecutor Paul Ebert and Fairfax County Police Detective John Kelly said the case would have been solved years ago if Virginia had used familial DNA searching. Aaron Thomas, the suspected East Coast Rapist, was arrested in connection with the rape of 17 women from Virginia to Rhode Island, but familial DNA was not used in the case. [ 69 ]


Critics of familial DNA database searches argue that the technique is an invasion of an individual's  4th Amendment  rights. [ 70 ]  Privacy advocates are petitioning for DNA database restrictions, arguing that the only fair way to search for possible DNA matches to relatives of offenders or arrestees would be to have a population-wide DNA database. [ 50 ]  Some scholars have pointed out that the privacy concerns surrounding familial searching are similar in some respects to other police search techniques, [ 71 ]  and most have concluded that the practice is constitutional. [ 72 ]  The  Ninth Circuit Court of Appeals  in  United States v. Pool  (vacated as moot) suggested that this practice is somewhat analogous to a witness looking at a photograph of one person and stating that it looked like the perpetrator, which leads law enforcement to show the witness photos of similar looking individuals, one of whom is identified as the perpetrator. [ 73 ]


Critics also state that racial profiling could occur on account of familial DNA testing. In the United States, the conviction rates of racial minorities are much higher than that of the overall population. It is unclear whether this is due to discrimination from police officers and the courts, as opposed to a simple higher rate of offence among minorities. Arrest-based databases, which are found in the majority of the United States, lead to an even greater level of racial discrimination. An arrest, as opposed to conviction, relies much more heavily on police discretion. [ 50 ]


For instance, investigators with Denver District Attorney's Office successfully identified a suspect in a property theft case using a familial DNA search. In this example, the suspect's blood left at the scene of the crime strongly resembled that of a current  Colorado Department of Corrections  prisoner. [ 63 ]


Partial DNA matches are the result of moderate stringency CODIS searches that produce a potential match that shares at least one  allele  at every  locus . [ 74 ]  Partial matching does not involve the use of familial search software, such as those used in the United Kingdom and the United States, or additional  Y-STR  analysis and therefore often misses sibling relationships. Partial matching has been used to identify suspects in several cases in both countries [ 75 ]  and has also been used as a tool to exonerate the falsely accused.  Darryl Hunt  was wrongly convicted in connection with the rape and the murder of a young woman in 1984 in  North Carolina . [ 76 ]


Police forces may collect DNA samples without a suspect's knowledge, and use it as evidence. The legality of the practice has been questioned in  Australia . [ 77 ]


In the  United States , where it has been accepted, courts often rule that there is no  expectation of privacy  and cite  California v. Greenwood  (1988), in which the  Supreme Court  held that the  Fourth Amendment  does not prohibit the  warrantless  search and seizure of  garbage  left for collection outside the  curtilage  of a  home . Critics of this practice underline that this analogy ignores that "most people have no idea that they risk surrendering their genetic identity to the police by, for instance, failing to destroy a used coffee cup. Moreover, even if they do realize it, there is no way to avoid abandoning one's DNA in public." [ 78 ]


The United States Supreme Court ruled in  Maryland v. King  (2013) that DNA sampling of prisoners arrested for serious crimes is constitutional. [ 79 ] [ 80 ] [ 81 ]


In the  United Kingdom , the  Human Tissue Act 2004  prohibits private individuals from covertly collecting biological samples (hair, fingernails, etc.) for DNA analysis but exempts medical and criminal investigations from the prohibition. [ 82 ]


Evidence from an expert who has compared DNA samples must be accompanied by evidence as to the sources of the samples and the procedures for obtaining the DNA profiles. [ 83 ]  The judge must ensure that the jury must understand the significance of DNA matches and mismatches in the profiles. The judge must also ensure that the jury does not confuse the match probability (the probability that a person that is chosen at random has a matching DNA profile to the sample from the scene) with the probability that a person with matching DNA committed the crime. In 1996  R v. Doheny [ 84 ]


Juries should weigh up conflicting and corroborative evidence, using their own common sense and not by using mathematical formulae, such as  Bayes' theorem , so as to avoid "confusion, misunderstanding and misjudgment". [ 85 ]


In  R v Bates , [ 86 ]  Moore-Bick LJ said:


We can see no reason why partial profile DNA evidence should not be admissible provided that the jury are made aware of its inherent limitations and are given a sufficient explanation to enable them to evaluate it. There may be cases where the match probability in relation to all the samples tested is so great that the judge would consider its probative value to be minimal and decide to exclude the evidence in the exercise of his discretion, but this gives rise to no new question of principle and can be left for decision on a case by case basis. However, the fact that there exists in the case of all partial profile evidence the possibility that a "missing" allele might exculpate the accused altogether does not provide sufficient grounds for rejecting such evidence. In many there is a possibility (at least in theory) that evidence that would assist the accused and perhaps even exculpate him altogether exists, but that does not provide grounds for excluding relevant evidence that is available and otherwise admissible, though it does make it important to ensure that the jury are given sufficient information to enable them to evaluate that evidence properly. [ 87 ]


There are state laws on DNA profiling in all 50  states  of the  United States . [ 88 ]  Detailed information on database laws in each state can be found at the  National Conference of State Legislatures  website. [ 89 ]


In August 2009, scientists in  Israel  raised serious doubts concerning the use of DNA by law enforcement as the ultimate method of identification. In a paper published in the journal  Forensic Science International: Genetics , the Israeli researchers demonstrated that it is possible to manufacture DNA in a laboratory, thus falsifying DNA evidence. The scientists fabricated saliva and blood samples, which originally contained DNA from a person other than the supposed donor of the blood and saliva. [ 90 ]


The researchers also showed that, using a DNA database, it is possible to take information from a profile and manufacture DNA to match it, and that this can be done without access to any actual DNA from the person whose DNA they are duplicating. The synthetic DNA  oligos  required for the procedure are common in molecular laboratories. [ 90 ]


The New York Times  quoted the lead author, Daniel Frumkin, saying, "You can just engineer a crime scene ... any biology undergraduate could perform this". [ 90 ]  Frumkin perfected a test that can differentiate real DNA samples from fake ones. His test detects  epigenetic  modifications, in particular,  DNA methylation . [ 91 ]  Seventy percent of the DNA in any human genome is methylated, meaning it contains  methyl group  modifications within a  CpG dinucleotide  context. Methylation at the promoter region is associated with gene silencing. The synthetic DNA lacks this  epigenetic  modification, which allows the test to distinguish manufactured DNA from genuine DNA. [ 90 ]


It is unknown how many police departments, if any, currently use the test. No police lab has publicly announced that it is using the new test to verify DNA results. [ 92 ]


Researchers at the University of Tokyo integrated an artificial DNA replication scheme with a rebuilt gene expression system and micro-compartmentalization utilizing cell-free materials alone for the first time. Multiple cycles of serial dilution were performed on a system contained in microscale water-in-oil droplets. [ 93 ]


Chances of making DNA change on purpose