C9orf135  is a gene that encodes a 229  amino acid  protein. It is located on  Chromosome 9  of the  Homo sapiens  genome at  9q12.21 . [ 5 ]  The protein has a  transmembrane  domain from amino acids 124-140 and a  glycosylation  site at amino acid 75. C9orf135 is part of the GRCh37 gene on Chromosome 9 and is contained within the  domain of unknown function  superfamily 4572. [ 6 ]  Also, c9orf135 is known by the name of LOC138255 which is a description of the gene location on Chromosome 9.1. [ 7 ]


There is some evidence associating the c9orf135 gene with premature ovarian failure. [ 8 ]  In affected women, an autosomal recessive microduplication occurs which may be linked to premature ovarian failure. A  Single Nucleotide Polymorphism  (SNP) the c9orf135 gene has been linked to  Parkinson's disease ; a statistically significant mutation has been seen on a  Manhattan plot . [ 9 ]  Further research is required to establish whether c9orf135 relates to Parkinson's disease. [ 9 ]


The mRNA of c9orf135 is 906 nucleotides in length. [ 10 ]  The 5' and 3' Untranslated regions (UTR) contain hairpin loops. [ 11 ]  The 3' UTR comprises 123 nucleotides and the 5' UTR comprises 18 nucleotides. The mRNA encodes a protein with a secondary structure composed of both beta-sheets and alpha-helices. [ 12 ]


It is likely that c9orf135 is a nuclear protein because it has properties that match attributes of nuclear proteins rather than secretory pathways. [ 13 ] [ 14 ]  Furthermore, there is a nuclear localization signal (PEKVKKL) from amino acid 67 to 73 on c9orf135. [ 15 ]  C9orf135 is soluble with an average hydrophobicity of -0.772. The negative hydrophobicity value is due to its slightly acidic properties. [ 16 ]


Serine  phosphorylation  sites were seen at amino acid positions 7, 50, 86, 98, and 194. Threonine phosphorylation occurs at 34, 129, 155, and 201.  Tyrosine phosphorylation  sites occur at 78, 160, 177, and 209. Also, a  N-terminal acetylation  site is present at amino acid 3. A Signal cleavage site is present between amino acids 11 and 12. [ 17 ]


PB2 interacts with c9orf135 which was found from a two-hybrid yeast assay. The information provided about PB2 (Polymerase Basic Protein 2) is that it is a viral protein that is involved with the  influenza A virus . It is primarily involved in  Cap  stealing in which it binds the pre-mRNA cap an ultimately cleaves 10-13 nucleotides off. PB2 is also important for starting the replication of viral genomes. PB2 is also known to inhibit type 1 interferon by inhibiting the mitochondrial antiviral signalling protein  MAVS . [ 18 ]


Eleven different common DNA genome variants of the human c9orf135 gene have been identified. All of the mutations within those genome variants have been compiled into the following table. [ 19 ]  Mutations that were present at levels of 0.01 frequency or higher have been incorporated into the table;  synonymous mutations  were excluded.


c9orf135 is expressed in connective tissue and testicular tissue at high levels. [ 20 ]  It is likely that the expression of c9orf135 is expressed at low levels throughout human cells. It was also found that c9orf135 is found at significantly higher levels in the adult human umbilical cord versus the foetal human umbilical cord. [ 21 ]  Furthermore, in women with  ovarian adenocarcinoma  the expression of c9orf135 is much higher in the epithelial cells within the ovaries. [ 22 ]  Women with  polycystic ovarian syndrome  have a lower expression of c9orf135 than those people who do not have the condition. [ 23 ]


A comparison between the c9orf135 from  Mus musculus  (House Mouse) and  Pteropus alecto  (Black Flying Fox) is described here. There were no significant amino acids that differed in c9orf135 from the rest of the mouse body. However, in the Black Flying Fox, it was valine poor and tryptophan rich. As seen from the human results, the Black Flying fox only shared the tryptophan surplus results. The House Mouse and Black Flying Fox were both used because they shared 64% and 79% similarity in the c9orf135 genome respectively. Analysis demonstrates that alanine and tyrosine could predict points of interest because they both contained results differing from the rest of the human gene averages. [ 16 ]


Compared to normal protein amounts in  H. sapiens


c9orf135 is conserved through eukaryotes, ranging from mammals, reptiles and  Annelida .


The orthologs of c9orf135 were sequenced in BLAST and 20 orthologs were picked. The orthologs were all multicellular organisms and were limited to aquatic animals, reptiles, amphibians, and warm-blooded animals. Also, protists, bacteria, archea, and fungi did not have orthologs. However, no paralogs were found when c9orf135 was sequenced in BLAST. Please refer to the spreadsheet for the complete list of orthologs to c9orf135. Time tree was a program that was used to find the evolutionary branching shown in MYA [ 24 ]  There were no paralogs found for c9orf135.


A divergence comparison of c9orf135 with fast diverging  cytochrome C , and slow diverging  fibrinogen  is shown in the chart. Overall, c9orf135 has diverged significantly quicker than fibrinogen and slightly slower than cytochrome C.


Chromosome 9


NM_001386868 NM_001386869 NM_001386871 NM_001386872


NP_001092806 NP_001265348 NP_001265349 NP_940923


Chromosome 12 Open Reading Frame 42  ( C12orf42 ) is a  protein -encoding  gene  in  Homo sapiens .


The genomic location for this gene is as follows: starts at 103,237,591 bp and ends 103,496,010 bp. [ 4 ]  The cytogenetic location for C12orf42 is 12q23.2. It is located on the negative strand [ 5 ]


Fifteen different mRNAs are made by transcription: fourteen alternative splice variants and one unspliced form. [ 5 ]


The protein released by this gene is known as uncharacterized protein C12orf42. [ 4 ]  There are three isoforms for this protein produced by alternative splicing. The first isoform is a  conical sequence . The second Isoform differs form the first in that it doesn't contain 1-95 aa in its sequence. The third isoform differs from the conical sequence in two ways: [ 8 ]


C12orf42 protein takes on several secondary structures, such as:  alpha helices ,  beta sheets , and  random coils . C12orf42 protein is a soluble. [ 9 ]  Proteins that are soluble have a hydrophilic outside and hydrophobic interior . [ 10 ]  Proteins with this type of structure are able to freely float inside a cell, due to the liquid composition of the  cytosol .


C12orf42 is an intracellular protein. This is known by the lack of transmembrane domains or signal peptides. This suggests that it is predicted to be a nuclear protein, given the  nuclear localization signal  (NSL) found: PRDRRPQ at 292 aa and a bipartite KRLIKVCSSAPPRPTRR at 325 aa.


Predicted post-translation modification sites are seen below in the table. Nuclear proteins are known for having phosphorylation, acetylation, sumoylation, and O-GlcNAc as types of modifications: [ citation needed ]


Ser302,Thr17,Thr45,Thr145,Thr150,Thr228,


Thr240,Thr240,Thr291,Thr339,Thr344,Tyr124 [ 11 ]


Ser217,Thr339 [ 14 ]


Microarray data  shows expression of the C12orf42 gene in different tissues throughout the human body. There is high expression in the  lymph node ,  spleen , and  thymus . [ 15 ]  There is significant expression in the  brain ,  bladder ,  epididymis , and the  helper T cell . [ 15 ]  Therefore, there is statistically significant expression of C12orf42 gene throughout the  nervous system ,  immune system , and  male reproductive system .


The table below shows the areas in the mouse brain where C12orf42 is expressed. The gene name for the mouse is 1700113H08Rik, it is the human  homolog  of C12orf42. [ 16 ]  Area one and two of the brain manages body and skeletal movement. Areas three and four in the brain are for sensory functions; area four specializes in perception of smell. Area five in the brain functions in emotional learning and memory.


C12orf42 gene has only one other member in its gene family, this gene is known as Neuroligin 4, Y linked gene (NLGN4Y). [ 18 ]


C12orf42  orthologs  are mostly mammals. One exception that was found is the  Pelodiscus Sinensis  or more commonly known as the Chinese soft-shell turtle.


The domain structure that is most important is DUF4607, it is conserved in the  Eutheria clade  in the Mammalia class. The order that it is conserved in is as follows:  Artiodactyla ,  Carnivora ,  Chiroptera ,  Lagomorpha ,  Perissodactyla ,  Primates ,  Proboscidea , and  Rodentia .


In an experiment, fine-tiling comparative genomic hybridization (FT-CGH) and ligation-mediated PCR (LM-PCR) were combined. [ 19 ]  This resulted in the finding of a chromosomal translocation t(12;14)(q23;q11.2) in   T-lymphoblastic lymphoma  (T-LBL). The chromosomal translocation occurs during  T-receptor delta gene-deleting rearrangement , which is important in T-cell differentiation. This translocation disrupts C12orf42 and it brings the gene  ASCL1  closer to the  T-cell receptor alpha  (TRA) enhancer. As a result, the cross-fused gene encodes vital  transcription factors  that are found in  medullary thyroid cancer  and  small-cell lung cancer .


NM_017970 NM_199043


NM_001290303 NM_183155 NM_001377383


NP_001277232 NP_898978 NP_001364312


Chromosome 14  open reading frame  102  (accession: AK294958; alias:  C14orf102 , FLJ14051, FLJ10008, FLJ52106) [ 5 ]  is a 3810bp  protein - encoding   gene  that is highly conserved among its non-distant  orthologs .  It contains 20  introns  and 8 different  RNAs  - 7  splice variants  and 1 unspliced form - and is located on the reverse strand of  chromosome 14  (14q32.11). [ 6 ]   The protein encoded by this gene (accession: BAG58032) belongs to the UPF0614 family of Up-frameshift proteins and has a  molecular weight  of 132.417 kDa and  isoelectric point  of 7.88.  It is expected to have a  protein binding  function and localization in the  cytoplasm . [ 7 ]


According to EST profiles, C14orf102 is most highly expressed in the  esophagus  (98 TPM) and  trachea  (76), and is further expressed in multiple different tissues. [ 8 ]   However, the AceView summary suggests that this gene is expressed most highly in the  brain , followed by decreased expression in 81 separate tissues.  This is inferred in the reconstruction of the  mRNA  sequence, as well as  exon  sequencing, in that the majority of  cDNA   clones  used for each procedure were found in the brain.  This is consistent with  GenBank  record, which indicates that the cDNA clone was also isolated from  brain tissue .  The general expression of the gene is high, being 1.8 times that of average gene expression.


The protein contains five HAT ( histone acetyltransferase )  domains , a coiled coil domain, a domain of unknown function, a  lysine -rich region, and a  poly-lysine  and  serine  region.  Further post-translational modifications include  phosphorylation  and mono- methylation  sites. [ 9 ]  Because the protein is considered to be a part of a family of Up-frameshift proteins, it is expected to function in protein binding and to be located in the cytoplasm. Certain UPF proteins have been found to play a central role in the nonsense-mediated mRNA decay (NMD) pathway, which is responsible for identifying and degrading mRNA sequences that contain premature termination  codons  (PTCs) – sequences that encode truncated  amino acid  sequences. [ 10 ]


C14orf102 interacts with  RNPS1 , a gene encoding a protein that is known to be directly involved in  nuclear export  and surveillance of mRNA. [ 6 ]   Surveillance by the RNPS1 protein initiates NMD after identification of exported, PTC-containing mRNA.  Because  UPF0614  is expected to be located in the cytoplasm and function in protein binding, this interaction supports the potential role of UPF0614 in the NMD pathway.


C15orf39  is a  protein  that in humans is encoded by the Chromosome 15  open reading frame  15 (C15orf39)  gene .


C15orf39 is located on  chromosome 15  (15q24.2), spanning 16.53kb from 75487985 to 75504515 on the plus  DNA  strand. [ 1 ]  C15orf39 has three  exons , and seven  introns . [ 1 ] [ 2 ]


The coding sequence for the C15orf39  mRNA  is 4443  base pairs  long. [ 4 ]  The C15orf39 gene produces seven mRNA transcripts, with the longest coding isoform being 1047  amino acids  long, and the shortest being 27 amino acids which has a truncated  3'  end. [ 5 ]


C15orf39 is highly expressed in the  trigeminal ganglion ,  superior cervical ganglion ,  whole blood , and the  heart . Low expression levels of C15orf39 were found in the  occipital lobe  and PB-CD19+  B-cells . [ 6 ]


C15orf39 expression levels in  fetal  and adult  reticulocytes  showed significantly different levels of expression (P < 0.0001), with adult reticulocytes expressing more C15orf39 than fetal cells. [ 7 ]


C15orf39 has an unmodified  molecular mass  of 110.6 kDA. [ 2 ] [ 8 ]  The modified molecular mass is 110.7 kDA. [ 9 ]  C15orf39 is composed of an above average level of  proline  (≈17%), and is deficient in  isoleucine  (≈1%) and  asparagine  (≈1%). [ 10 ]  Both close ( Thirteen-lined ground squirrel ) and distant ( Crested-Ibis ) orthologs contained above average levels of proline, and low levels of isoleucine, and asparagine.


C15orf39 has four predicted domains. Two of which, are the  proline  rich and  alanine  rich domains. The large tegument protein UL36 domain is important in the regulation of the viral cycle of Human  Herpes Virus  1 (HHV-1), including transporting the viral  capsid  to the  nuclear pore complex , and linking the inner and outer viral tegument capsids together. [ 11 ]  Lastly, the  WH2 domain , WASP-homology domain 2, is approximately 18 amino acids long, and serves as an  actin  binding domain. [ 12 ]  WH2 binds actin monomers enabling the production of  actin filaments .


The predicted  post-translational modifications  for C15orf39 include  phosphorylation ,  acetylation ,  sumoylation , and  o-glycosylation . An amino acid of importance is K17, which has an acetyl and sumo-group covalently attached. [ 2 ] [ 13 ]  Also, T970, which is phosphorylated and has an o-glycosyl group attached. [ 14 ] [ 15 ]  All predicted post-translational modifications were conserved in distant and strict orthologs.


Alpha helices  predicted in the C15orf39 protein are colored red, and random coils are represented as tan. No  beta sheets  were predicted to be part of the  secondary structure  for C15orf39. The amino acids not modeled were predicted to be  random coils . [ 16 ]


C15orf39 is predicted to be located in the  cytosol  of the cell. [ 18 ]


Protein interaction screenings have showed C15orf39 to interact with many proteins, including RPLP1 and EIF4ENIF1. C15orf39 was discovered to interact with  RPLP1  (Large Ribosomal Subunit Protein P1), a  cytoplasmic  protein, in a high-output  yeast two-hybrid  screening. RPLP1 is an acidic  ribosomal  subunit that is important in the elongation step of  transcription . [ 19 ] [ 20 ]   EIF4ENIF1  (Eukaryotic Translation Initiation Factor 4E Transporter), is a nucleocytoplasmic protein that shuttles the  translation  initiation factor eIF4E between the  nucleus  and cytoplasm. [ 21 ]  The protein interaction between C15orf39 and EIF4ENIF1 was discovered through  affinity capture . [ 22 ]


There are no known  paralogs  for the human C15orf39 gene. [ 23 ]


The  ortholog  space for C15orf39 includes relatives as distant as the  cartilaginous fish  like  Rhincodon typus  ( whale shark ), and as strict as closely related mammals like the  Gorilla , which has 99% sequence identity to the human protein. [ 24 ] [ 25 ]  The  phylogenetic tree  below, shows the  evolutionary  relationship of the C15orf39 protein sequence in its orthologs. [ 26 ]


The graph displays that the C15orf39 protein is quickly  evolving . C15orf39's sequence has diverged at a quicker rate than the quickly evolving  fibrinogen  protein in humans. [ 27 ]


C20orf96  ( Chromosome 20 open reading frame 96 ) is a protein-coding gene in humans. [ 1 ]  It codes for an unknown protein known as  uncharacterized protein C20orf96 , predicted to be a  nuclear protein . The function and biological processes of the gene is not well understood by the scientific community yet.


C20orf96 is also known by the alias DJ1103G7.2. Orthologs found in other organisms are known as C20orf96 homolog isoform X [Species].


C20orf96 is located on the short arm of chromosome 20 at 20p13, base pairs 270,863 to 290,778 on the complementary strand. It is a member of the DUF4618  superfamily , with the DUF position being from amino acid 104 to 363. [ 1 ]  Neighboring genes are DEFB129, DEFB132, ZCCHC3, and NRSN2-AS1.


Aceview states that the gene is expressed 2.2 times the amount an average gene is expressed, and the sequence has been seen in the brain, testis, uterus, kidney, thymus, breast, kidney tumor, and 84 other places. [ 2 ]  C20orf96 has been found to bind to transcription factor binding sites AREB6, GATA-1, GATA-2, GATA-3, ATF6, c-Myc, Max, CHOP-10, AMLa, and C/EBPalpha. [ 3 ]   TYW5 and ALOXE3 are two proteins that interact with C20orf96. TYW5 is a protein coding gene and also incorporates tRNA modification in the nucleus. [ 4 ]  ALOXE3 is also a protein coding gene, more focusing on Prostaglandin 2 biosynthesis. [ 5 ]


C20orf96 can be split up into five different variants. All variants code for similar proteins. The variant used for this article was Variant 1. The splicing is shown below.


The protein made by C20orf96 is 363 amino acids in length. The predicted  molecular weight  is 42.9 kdal, and the  isoelectric point  is 8.99. [ 6 ] [ 7 ]


The ratios of this protein are similar to others. The unusual amounts of amino acids are found as alanine, glutamic acid, glycine, and glutamine. Glutamic acid and glutamine both have a slightly larger amount than normal, alanine is slightly below normal, and glycine is low compared to other proteins.


C20orf96 has a neutral charge, with no additional positive, negative, or mixed charge clusters.


NetPhos predicts 10 serine sites, 4 threonine sites, and 3 tyrosine sites over the 363 amino acids. [ 8 ]  No signal peptides were detected. There were also no transmembrane sequences.


Most of the structure is made up of alpha-helices, with short coils on both ends. At the end of the sequence, there is also a small, four amino acid beta-strand.


There are no known crystal structures for this protein. The tertiary structure is mainly composed of coiled-coil regions.


C20orf96 is found in many eukaryotes. Orthologs have been found in most organisms in the kingdom animalia, with the lineage going back to the phylum Chordata. No paralogs for C20orf96 have been found.


The most prevalent mutations of C20orf96 in humans are M1V, Q6K, T13I, T13S, M94I, S117G, S117T, S117N, L142V, D159N, M215T, D238E, R251C, R251G, Q263E, R279C, E304G, I305F, M313I, R328W, R342I, and L353V. The format these mutations are given in are the amino acid that is supposed to be there, the amino acid number, and then the mutation.


C20orf96 has been linked to Moyamoya Disease, increasing the odds of contracting the disease by 4.5 times. [ 9 ]  It is also associated with lymph node metastasis in colorectal cancer. [ 10 ]  A study found that C20orf96 has shown positive selection for containing a hub gene, which is a gene that is ranked in the top 20 for connectivity. [ 11 ]


Calcium channel associated transcriptional regulator  (CCAT) is a  transcription factor  found in mammalian cells.


In neuronal cells, CCAT is generated upon activation of a cryptic promoter in exon 46 of  CACNA1C , the gene that encodes the voltage-gated calcium channel  Cav1.2 . [ 1 ]


This  gene  article is a  stub . You can help Wikipedia by  expanding it .


NM_001753 NM_001172895 NM_001172896 NM_001172897


NM_001243064 NM_007616


NP_001166366 NP_001166367 NP_001166368 NP_001744


NP_001229993 NP_031642


Caveolin-1  is a  protein  that in humans is encoded by the  CAV1   gene . [ 5 ]


The scaffolding  protein  encoded by this  gene  is the main component of the  caveolae  plasma membranes found in most cell types. The protein links integrin subunits to the tyrosine kinase FYN, an initiating step in coupling integrins to the Ras-ERK pathway and promoting cell cycle progression. The gene is a  tumor suppressor  gene candidate and a negative regulator of the Ras-p42/44 MAP kinase cascade. CAV1 and  CAV2  are located next to each other on  chromosome 7  and express colocalizing proteins that form a stable hetero-oligomeric complex. By using alternative initiation  codons  in the same reading frame, two isoforms (alpha and beta) are encoded by a single transcript from this gene. [ 6 ]


Caveolin 1 has been shown to  interact  with  heterotrimeric G proteins , [ 7 ]
Src tyrosine kinases ( Src ,  Lyn ) and H-Ras, [ 8 ]
 cholesterol , [ 9 ]
 TGF beta receptor 1 , [ 10 ]
 endothelial NOS , [ 11 ]
 androgen receptor , [ 12 ]
 amyloid precursor protein , [ 13 ]
 gap junction protein, alpha 1 , [ 14 ]
 nitric oxide synthase 2A , [ 15 ]   epidermal growth factor receptor , [ 16 ]   endothelin receptor type B , [ 17 ]   PDGFRB , [ 18 ]   PDGFRA , [ 18 ]   PTGS2 , [ 19 ]   TRAF2 , [ 20 ] [ 21 ]   estrogen receptor alpha , [ 22 ]   caveolin 2 , [ 23 ] [ 24 ]   PLD2 , [ 25 ] [ 26 ]   Bruton's tyrosine kinase , [ 27 ]  and  SCP2 . [ 28 ]  All these interactions are through a caveolin-scaffolding domain (CSD) within caveolin-1 molecule. [ 8 ]  Molecules that interact with caveolin-1 contain caveolin-binding motifs (CBM). [ 29 ]


Coiled-Coil Domain Containing 11 , also known as  CCDC11  is a  protein , that is encoded by  CCDC11   gene  located at chromosome 18 in humans. [ 1 ]


The CCDC11 gene is located on chromosome 18q21.1 and is made of 39303 BP. [ 2 ]  The CCDC11 protein is made of 514 amino acids and has a mass of 61835 Da. [ 2 ]   Its aliases include coiled-coil domain containing protein 11, FLJ32743, OTTHUMP00000163503. [ 2 ]


CCDC has orthologs all the way back to betaproteobacteria which is a class of Proteobacteria. [ 2 ]  The following table represents a small selection of orthologs found using searches in BLAST and BLAT.  This is by no means a comprehensive list; however, it shows the diversity of species that CCDC11 is found.


The below image from NCBI shows the gene neighborhood of CCDC11 on chromosome 18.  CCDC11 has methyl-CPG binding domain protein 1, MBD1, upstream and myosin VB3, MYO5B, downstream.  All CCDC11, MBD1 and MYO5B are oriented negatively.  Note the close proximity between MBD1 and CCDC11.


Tools on the ExPASy Proteomics site [ 3 ]  predict the following post-translational modifications:


One tool on the ExPASy, iPSORT, showed no signal peptide;however, it indicated CCDC11 to be mitochondrial.  Another tool on the ExPASy, SOSUI, indicated the protein to be a soluble protein.


CCDC116 , also called coiled-coil domain containing 116, is a gene that is patented for experimentation on the possibility of being a cancer marker for prostate cancer.


CCDC116 has no aliases. [ 1 ]  This gene is 2252 base pairs long. [ 2 ]  CCDC116 has 5  exons  and is located on chromosome 22q11.21 on the plus strand. [ 3 ]


CCDC116 has two  isoforms . [ 3 ]  The isoforms differ in the 3’ UTR and coding sequence. [ 3 ]


CCDC116 is 612  amino acids  long. [ 1 ]   CCDC116 is 67.9 kdal. [ 1 ]  This protein has an  isoelectric point  of 9.24. [ 1 ]  This protein is a part of the domain of unknown function 4702. [ 1 ]


It is predicted that CCDC116 is located in the nucleus. [ 4 ]   It is predicted that the membrane typology of this protein is a type 3a rolled up  beta sheet . [ 4 ]  This protein has mostly  alpha helices  with a few coils. [ 4 ]


CCDC116 is primarily found in the testis, although this gene is found in very small amounts in the brain and connective tissue. [ 1 ]  There are two  SNPs  that are upstream variants, one that is a downstream variant, one that is an intron variant. [ 1 ]


CCDC116 has four promoter regions and eight primary transcripts. [ 5 ]  Two promoter regions located on the + strand, and two located on the - strand. [ 5 ]


CCDC116 has two predicted function partners.  NGFRAP is a nerve growth factor receptor associated protein. [ 1 ]   This gene is believed to play a role in the  pathogenesis  of neurogenetic diseases, although that claim has not been proven. [ 1 ]


There has yet to be any disease association with CCDC116, but currently there is a patent for this gene with the potential for it to be related to cancer. [ 6 ]  A study was done in 2012 on observing how this gene is expressed in human  pancreatic islets  and in  endocrine  pancreatic tumors. [ 7 ]


n a


Coiled-coil domain containing protein 180  (CCDC180) is a  protein  that in  humans  is encoded by the  CCDC180   gene . [ 2 ]   This protein is known to localize to the  nucleus  and is thought to be involved in regulation of  transcription  as are many proteins containing  coiled-coil  domains.  As it is expressed most highly in the  testes  and is regulated by  SRY  and  SOX   transcription factors , it could be involved in  sex determination .


CCDC180  is located on  chromosome 9  at the locus 9q22.33. [ 2 ]


CCDC180 is also known by the aliases KIAA1529, BDAG1 ( Behçet's Disease  Associated Gene 1), and C9orf174. [ 2 ]


The  CCDC180  gene is 71,221 bases long.  It contains 37  exons  and is oriented on the forward strand of the chromosome. [ 3 ]


There are no known  isoforms  or alternative splicing variants of the CCDC180  mRNA . [ 3 ]


CCDC180 contains 1,701  amino acids [ 4 ]  and has a  molecular weight  of 197.3  kDa . The  isoelectric point  (pI) is 5.74.  The low pI is attributed to a relatively high concentration of  glutamic acid  when compared to other human proteins at 12.9%. CCDC180 also contains a relatively low concentration of  glycine  when compared to the average human protein at 3.5%. [ 5 ]


CCDC180 contains two  domains of unknown function (DUFs) : DUF4455 and DUF4456.  There are also two  coiled-coil  regions which overlap with the DUFs.  There is a region of low complexity that is very rich in  glutamic acid .


The  secondary structure  of CCDC180 is predicted to be almost completely composed of  alpha helices , with only a few predicted  beta sheets . [ 7 ]   The  tertiary structure  is not completely characterized as yet, but a model predicted by the  I-TASSER  server at the  University of Michigan  is pictured.


CCDC180 is predicted to undergo a variety of  post-translational modifications :


CCDC180 is predicted to localize to the  nucleus , and it contains four  nuclear localization sequences . [ 12 ]


CCDC180 is expressed ubiquitously at low levels throughout the body, and the highest expression is consistently seen to be in the  testes .  Other replicated tissues of high expression include the  trachea  and  eye . [ 13 ] [ 14 ]


Transcription  of  CCDC180  is predicted to be regulated by a 664 base pair  promoter  region, with the ID GXP_1829211.  This prediction is supported by the transcripts GXT_23217882, GXT_24495001, GXT_24495002, and GXT_24495003.  Transcription factors  predicted to bind to this promoter region are described below. [ 15 ]


The following proteins have been shown to interact with CCDC180 in  yeast two-hybrid assays . [ 16 ]


A  single-nucleotide polymorphism  (SNP) in the gene that leads to a single  amino acid  change (S995C) has been shown in a  genome-wide association study  to be significantly associated with  Behçet's disease , and this designation led to the alias  Behcet's disease -associated gene 1 (BDAG1). [ 36 ]   The role of CCDC180 in the disease phenotype is unknown.


There are no paralogs in humans for this gene, but there are orthologs in a wide variety of organisms, extending back to single-celled green algae. CCDC180 is not conserved in  bacteria ,  archaea ,  plants ,  fungi , or  protists . The following table includes a subset of species containing protein orthologs of CCDC180. It is not exhaustive, but it indicates the variety of species containing orthologs of CCDC180.


Humans [ 37 ]


Length


CCDC180 is a relatively quickly-evolving gene compared to other well-known genes. There are no known family members, splice variants or isoforms, or evidence of gene duplications in the history of the gene.


2A5E ,  1A5E ,  1BI7 ,  1DC2 ,%%s 1A5E ,  1BI7 ,  1DC2 ,  2A5E


P42771 Q8N726


P51480 Q64364


NM_001040654 NM_009877


NP_001035744 NP_034007 NP_034007.1


CDKN2A , also known as  cyclin-dependent kinase inhibitor 2A , is a  gene  which in humans is located at  chromosome 9 , band p21.3. [ 5 ]  It is ubiquitously expressed in many tissues and cell types. [ 6 ]  The gene codes for two  proteins , including the  INK4 family  member  p16  (or p16INK4a) and  p14arf . [ 7 ]  Both act as  tumor suppressors  by regulating the  cell cycle . p16 inhibits cyclin dependent kinases 4 and 6 ( CDK4  and  CDK6 ) and thereby activates the  retinoblastoma  (Rb) family of proteins, which block traversal from  G1  to  S-phase . p14ARF (known as p19ARF in the mouse) activates the  p53  tumor suppressor. Somatic mutations of  CDKN2A  are common in the majority of human cancers, with estimates that  CDKN2A  is the second most commonly inactivated gene in cancer after  p53 .  Germline mutations  of  CDKN2A  are associated with familial  melanoma ,  glioblastoma  and  pancreatic cancer . [ 8 ]  The  CDKN2A  gene also contains one of 27  SNPs  associated with increased risk of  coronary artery disease . [ 9 ]


The  CDKN2A  gene resides on chromosome 9 at the band 9p21 and contains 8  exons . [ 10 ]  This gene encodes two proteins,  p16  and  p14ARF , which are transcribed from the same second and third exons but alternative first exons: p16 from exon 1α and ARF from exon 1β. As a result, they are translated from different  reading frames  and therefore possess completely different  amino acid sequences . [ 11 ]  In addition to p16 and ARF, this gene produces 4 other  isoforms  through  alternative splicing . [ 12 ]


This protein belongs to the CDKN2  cyclin-dependent kinase inhibitor  family. [ 12 ]  p16 comprises four  ankyrin repeats , each spanning a length of 33 amino acid residues and, in the  tertiary structure , forming a  helix-turn-helix motif . One exception is the second ankyrin repeat, which contains only one helical turn. These four motifs are connected by three loops such that they are oriented perpendicular to the helical axes.


According to its  solvent -accessible surface representation, p16 features clustered charged groups on its surface and a pocket located on the right side with a  negatively charged  left inner wall and a  positively charged  right inner wall. [ 13 ]


The size of this protein is 14  kDa  in humans. [ 14 ]  Within the  N-terminal  half of ARF are highly  hydrophobic  domains that serve as  mitochondrial  import sequences.


P14ARF is a central actor of the cell cycle regulation process as it participates to the ARF- MDM2 -p53 pathway and the Rb- E2F -1 pathway. [ 15 ]  It is the physiological inhibitor of MDM2, an E3 ubiquitin ligase controlling the activity and stability of P53, and loss of P14ARF activity may have a similar effect as loss of P53. [ 16 ]  P14ARF induces cell cycle arrest in  G2 phase  and subsequent  apoptosis  in a P53-dependent and P53-independent manner, and thus is regarded as a tumor suppressor. [ 17 ] [ 18 ] [ 19 ] [ 20 ]  In addition, P14ARF could down-regulate E2F-dependent transcription and plays a role in the control of the G1 to S  phase transition  as well. [ 21 ]


P16 interacts with Rb and controls the G1 to S transition. It binds to  CDK4 /6 inhibiting its kinase activity and prevents Rb phosphorylation. Therefore, Rb remains associated with transcription factor E2F1, preventing transcription of E2F1 target genes which are crucial for the G1/S transition. During this process, a feedback loop exists between P16 and Rb, and P16 expression is controlled by Rb. [ 22 ] [ 23 ]  P16/Rb pathway collaborates with the mitogenic signaling cascade for the induction of  reactive oxygen species , which activates the  protein kinase C delta , leading to an irreversible cell cycle arrest. Thus P16 participates not only in the initiation but also in the maintenance of cellular senescence, as well in tumor suppression. [ 24 ] [ 25 ]  On the other hand, some specific tumors harbor high levels of P16, and its function in limitation of tumorigenic progression has been inactivated via the loss of Rb. [ 25 ] [ 26 ]


In human cancer cell lines derived from various tumor types, a high frequency of genetic and epigenetic alterations (e.g., promoter hyper-methylation, homozygous deletion or mutation) in the  CDKN2A  gene has been observed. Accordingly, epigenetic/genetic modulation of changes in  CDKN2A  might be a promising strategy for prevention or therapy of cancer.


The  CDKN2A  gene is located on the chromosome 9p21 locus, which is intriguing for several reasons. First, this region is well known in cancer genetics as one of the most common sites of deletions leading to hereditary forms of cutaneous malignant melanoma. [ 11 ] [ 27 ]  Second, genome wide association studies have reported a significant association of chromosome 9p21 with coronary artery disease and myocardial infarction [ 28 ]  as well as the progression of atherosclerosis. [ 29 ]


Furthermore, changes in  CDKN2A  status are highly variable depending on the type of cancer. In addition to skin cancer such as melanoma, changes of  CDKN2A  have been described in a wide spectrum of cancer types such as gastric lymphoma, [ 30 ]  Burkitt's lymphoma, [ 31 ]  head & neck squamous cell carcinoma, [ 32 ]  oral cancer, [ 33 ]  pancreatic adenocarcinoma, [ 34 ]  non-small cell lung carcinoma, [ 35 ]  esophageal squamous cell carcinoma, [ 36 ]  gastric cancer, [ 37 ]  colorectal cancer, [ 38 ]  epithelial ovarian carcinoma [ 39 ]  and prostate cancer. [ 40 ]


CDKN2A  is made up of four sections of exons – exon 1β, exon 1α, exon 2, and exon 3. These exons are used to create two proteins named p16 and p14ARF. Protein p16, created by exon 1α and exon 2, is responsible for tumor creation of genetic melanoma. When working normally, p16 binds to the cyclin dependent kinases CDK4 to inhibit their ability to create tumors, but when inactivated the suppression no longer occurs. [ 41 ]  When a mutation occurs in protein p16, it prevents the protein kinase of CDK4, which results in the inactivation of the tumor suppressor gene. [ 41 ]  This starts the development of  melanoma .


Melanoma only occurs in a small proportion of the population. If only two family members have melanoma, there is a 5% chance somebody in the next generation will acquire the mutated gene. Also, there is a 20-40% chance of getting hereditary melanoma in a family if 3 or more people in the past generation had melanoma. For those who carry the hereditary mutated gene  CDKN2A , acquiring skin cancer is a lot easier. [ 42 ]  Those who have the gene are far more likely to get melanoma a second or third time compared to those who don't genetically have this gene. [ 43 ]  The population that is affected by this mutation has a high familial history of melanoma or atypical moles and birth marks in large numbers, a history of primary melanoma/cancers in general,  immunosuppression , skin that burns easily and doesn't tan, freckling, blue eyes, red hair, or a history of blistering. [ 42 ]  People with these high risk factors are more likely to carry inherited mutations in  CDKN2A . [ 43 ]  For those who have a gene mutation, the severity is also dependent on the environmental surroundings. Out of those who carry the gene, those who express the phenotype and actually developed melanoma have a history of more sun exposure, and light skin compared to those who also had the gene but never actually developed melanoma. [ 43 ]  This suggests that this gene co-works with ones surrounding environment. If two individuals are selected who carry the  CDKN2A  mutation, and both genetically have the same probability of acquiring skin cancer, but one is from Australia and the other is from Europe, there is a 58% the European will acquire cancer compared to a 91% chance the Australian will get it. [ 43 ]  This is because the factors mentioned earlier pertaining to those who are more susceptible to the disease and also dependent on the amount of sunscreen one wears and the UV radiation potency in their environment. [ 42 ]


A multi-locus genetic risk score study based on a combination of 27 loci, including the  CDKN2A  gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). [ 9 ]


Activation of the  CDKN2A  locus promotes the  cellular senescence  tumor suppressor mechanism, which is a permanent form of growth arrest. As senescent cells accumulate with aging, expression of  CDKN2A  increases exponentially with aging in all mammalian species tested to date, and has been argued to serve as a biomarker of physiological age. [ 44 ]  Notably, a recent survey of cellular senescence induced by multiple treatments to several cell lines does not identify  CDKN2A  as belonging to a "core signature" of senescence markers. [ 45 ]


A variant in the  CDKN2A  locus present in the founder of Bernese mountain dogs around 200 years ago predisposes the breed to  histiocytic sarcoma . [ 46 ]


NM_001256126 NM_203463


NM_172856 NM_001347161


NP_001243055 NP_982288


NP_001334090 NP_766444


Ceramide synthase 6  is a  protein  that in humans is encoded by the CERS6  gene .
 [ 5 ]


This article on a  gene  on human  chromosome 2  is a  stub . You can help Wikipedia by  expanding it .


ChimerDB  in  computational biology  is a database of  fusion sequences . [ 1 ]


ChimerDB currently consists of three searchable datasets. [ 2 ]


This  Biological database -related article is a  stub . You can help Wikipedia by  expanding it .


Chimeric genes  (literally, made of parts from different sources) form through the combination of portions of two or more  coding sequences  to produce new genes.  These  mutations  are distinct from  fusion genes  which merge whole gene sequences into a single reading frame and often retain their original functions.


Chimeric genes can form through several different means.  Many chimeric genes form through errors in  DNA replication  or  DNA repair  so that pieces of two different genes are inadvertently combined. [ 1 ]   Chimeric genes can also form through  retrotransposition  where a retrotransposon accidentally copies the transcript of a gene and inserts it into the genome in a new location.  Depending on where the new  retrogene  appears, it can recruit new  exons  to produce a chimeric gene.  Finally,  ectopic recombination , when there is an exchange between portions of the genome that are not actually related, can also produce chimeric genes.  This process occurs often in human genomes, and abnormal chimeras formed by this process are known to cause  color blindness .


Chimeric genes are important players in the evolution of genetic novelty.  Much like  gene duplications , they provide a source of new genes, which can allow organisms to develop new  phenotypes   and  adapt  to their environment.  Unlike duplicate genes, chimeric proteins are immediately distinct from their parental genes, and therefore are more likely to produce entirely new functions.


Chimeric fusion proteins form often in genomes, [ 1 ]  and many of these are likely to be dysfunctional and eliminated by natural selection.  However, in some cases, these new peptides can form fully functional gene products that are  selectively favored  and spread through populations quickly.


One of the most well known chimeric genes was identified in  Drosophila  and has been named  Jingwei . [ 2 ]   This gene is formed from a  retrotransposed  copy of  Alcohol dehydrogenase  that united with the yellow emperor gene to produce a new protein. [ 2 ]   The new amino acid residues that it recruited from yellow emperor allow the new protein to act on long chain alcohols and diols, including growth hormones and pheremones. [ 3 ]  These changes affect fly development.  In this case, the combination of different  protein domains  resulted in a gene that was fully functional and favored by selection.


The functions of many chimeric genes are not yet known. In some cases these gene products are not beneficial and they may even cause diseases such as cancer.


NM_017447 NM_001100420 NM_001100421


NM_001252438 NM_001252439 NM_001252440 NM_025967


NP_001093890 NP_001093891 NP_059143


NP_001239367 NP_001239368 NP_001239369 NP_080243


Chromosome 21 open reading frame 91  is a  protein  that in humans is encoded by the C21orf91  gene .
 [ 5 ]


EURL  is a  structural protein gene  that is encoded within the  human chromosome 21 . [ 6 ] [ 7 ]  It stands for gene Expressed in Undifferentiated Retina and Lens and was first found in  chick embryos . It is also known as C21orf 91 (Chromosome 21 open reading frame 91). [ 8 ]  This gene produces many molecules; among them is a protein that influences neural development. This protein-coding region helps to code for neural development in humans and is strongly associated with neural  progenitor cells  as well as neurons associated with the  cerebral cortex  of the brain. [ 6 ]


Thus, being on chromosome 21, defects linked to this gene are heavily correlated to  Down Syndrome . There are some knockout models regarding other genes involved in Down Syndrome, but there seems to be primary interest in a knockdown model for this specific gene. It is believed that because there is three codes of this gene rather than two, that the higher concentration of this molecule has the implications leading to Down Syndrome. Scientists are currently working on a hypothesis that the dosage of the EURL protein is directly correlated to neural development in the embryo and how an altered dosage leads to the neural deficits seen in Down Syndrome. [ 6 ]


This article on a  gene  on human  chromosome 21  is a  stub . You can help Wikipedia by  expanding it .


A  cistron  is a region of  DNA  that is conceptually equivalent to some definitions of a  gene , such that the terms are synonymous from certain viewpoints, [ 1 ]  especially with regard to  the molecular gene as contrasted with the Mendelian gene . The question of which scope of a subset of DNA (that is, how large a segment of DNA) constitutes a  unit of selection  is the question that governs whether cistrons are the same thing as genes. The word  cistron  is used to emphasize that molecular genes exhibit a specific behavior in a  complementation test  (cis-trans test); distinct positions (or  loci ) within a  genome  are  cistronic .


The words  cistron  and  gene  were coined before the advancing state of  biology  made it clear to many people that the concepts they refer to, at least in some senses of the word  gene , are either equivalent or nearly so. The same historical naming practices are responsible for many of the  synonyms  in the life sciences.


The term  cistron  was coined by  Seymour Benzer  in an article entitled  The elementary units of heredity . [ 2 ]  The cistron was defined by an operational test applicable to most organisms that is sometimes referred to as a cis-trans test, but more often as a  complementation test .


Richard Dawkins  in his influential book  The Selfish Gene  argues  against  the cistron being the  unit of selection  and against it being the best  definition of a gene . (He also argues against  group selection .) He does not argue against the existence of cistrons, or their being elementary, but rather against the idea that natural selection selects them; he argues that it used to, back in earlier eras of life's development, but not anymore. He defines a gene as a larger unit, which others may now call  gene clusters , as the unit of selection. He also defines replicators, more general than cistrons and genes, in this  gene-centered view of evolution .


Defining a Cistron as a segment of DNA coding for a polypeptide, the structural gene in a transcription unit could be said as monocistronic (mostly in eukaryotes) or polycistronic (mostly in bacteria and prokaryotes). For example, suppose a  mutation  at a chromosome position

 x

 {\displaystyle x}

  is responsible for a change in  recessive trait  in a  diploid  organism (where chromosomes come in pairs). We say that the mutation is recessive because the organism will exhibit the  wild type   phenotype  (ordinary trait) unless both chromosomes of a pair have the mutation ( homozygous  mutation). Similarly, suppose a mutation at another position,

 y

 {\displaystyle y}

 , is responsible for the same recessive trait. The positions

 x

 {\displaystyle x}

  and

 y

 {\displaystyle y}

  are said to be within the same cistron when an organism that has the mutation at

 x

 {\displaystyle x}

  on one chromosome and has the mutation at position

 y

 {\displaystyle y}

  on the paired chromosome exhibits the recessive trait even though the organism is not homozygous for either mutation. When instead the wild type trait is expressed, the positions are said to belong to distinct cistrons / genes. Or simply put, mutations on the same cistrons will not complement; as opposed to mutations on different cistrons may complement (see Benzer's T4 bacteriophage experiments  T4 rII system ).


For example, an  operon  is a stretch of DNA that is  transcribed  to create a contiguous segment of  RNA , but contains more than one cistron / gene. The operon is said to be polycistronic, whereas ordinary genes are said to be monocistronic.


A  class II gene  is a type of  gene  that codes for a  protein . Class II genes are  transcribed  by  RNAP II   [ citation needed ] .


Class II genes have a  promoter  that may contain a  TATA box .


Basal transcription of class II genes requires the formation of a  preinitiation complex .


They are transcribed by RNA polymerase II, include both intron and exon, and code for polypeptide.


Claudin-17  is a  protein  that in humans is encoded by the  CLDN17   gene . [ 5 ] [ 6 ]  It belongs to the group of  claudins ; claudins are cell-cell junction proteins that keep that maintains cell- and tissue-barrier function. [ 7 ]  It forms anion-selective  paracellular  channels and is localized mainly in  kidney  proximal tubules. [ 8 ] [ 9 ]


1E4U ,  1UR6


NM_013316 NM_001393370 NM_001393371 NM_001393372 NM_001393373 NM_001393374 NM_001393375


NM_001164411 NM_001164412 NM_001164413 NM_001164414 NM_016877


NP_001157883 NP_001157884 NP_001157885 NP_001157886 NP_058573


CCR4-NOT transcription complex, subunit 4  is a  protein  that in  humans  is encoded by the CNOT4  gene . [ 5 ]


The protein encoded by this gene is a subunit of the  CCR4-Not  complex, a global  transcriptional   regulator  and  deadenylase . The encoded protein interacts with  CNOT1  and has  ubiquitin ligase  activity. Several transcript variants encoding different  isoforms  have been found for this gene.[provided by RefSeq, Jul 2010].  Diseases associated with CNOT4 include Adenoiditis. [ 6 ]


2H0D ,  3RPG ,  4R8P


NP_001190991 NP_005171


The  COMMD3-BMI1   gene  in humans encodes the COMMD3-BMI1 readthrough  protein .
 [ 5 ]


This  locus  represents naturally occurring read-through  transcription  between the neighboring  COMM domain-containing protein 3  and  polycomb complex protein BMI-1  genes on  chromosome 10 . The read-through transcript produces a  fusion protein  that shares sequence identity with each individual gene product. [ 6 ]


This article on a  gene  on human  chromosome 10  is a  stub . You can help Wikipedia by  expanding it .


A  conjoined gene  (CG) is defined as a  gene , which gives rise to transcripts by combining at least part of one exon from each of two or more distinct known (parent) genes which lie on the same chromosome, are in the same orientation, and often (95%) translate independently into different proteins. In some cases, the transcripts formed by CGs are translated to form chimeric or completely novel proteins.


Several alternative names are used to address conjoined genes, including combined gene and complex gene, [ 1 ]   fusion gene ,  fusion protein , read-through transcript, co-transcribed genes, bridged genes, spanning genes, hybrid genes, locus-spanning transcripts, etc.


At present, 800 CGs have been identified in the entire human genome by different research groups across the world including Prakash et al., [ 2 ]  Akiva et al., [ 3 ]  Parra et al., [ 4 ]  Kim et al., [ 5 ]  and in the 1% of the human genome in the ENCODE pilot project. [ 6 ]  36% of all these CGs could be validated experimentally using RT-PCR and sequencing techniques. However, only a very limited number of these CGs are found in the public human genome resources such as the  Entrez Gene database , the  UCSC Genome Browser  and the  Vertebrate Genome Annotation (Vega) database . More than 70% of the human conjoined genes are found to be conserved across other vertebrate genomes with higher order vertebrates showing more conservation, including the closest human ancestor, chimpanzee. Formation of CGs is not only limited to the human genome but some CGs have also been identified in other eukaryotic genomes, including mouse and drosophila. There are a few web resources which include information about some CGs in addition to the other fusion genes, for example,  ChimerDB  and  HYBRIDdb . Another database,  ConjoinG , is a comprehensive resource dedicated only to the 800 Conjoined Genes identified in the entire human genome.


NP_004364 NP_004364.2


Cytochrome c oxidase subunit 6A1, mitochondrial  is a  protein  that in humans is encoded by the  COX6A1   gene . Cytochrome c oxidase 6A1 is a subunit of the cytochrome  c  oxidase complex, also known as  Complex IV , the last enzyme in the  mitochondrial   electron transport chain . A  mutation  of the COX6A1 gene is associated with a  recessive  axonal or mixed form of  Charcot-Marie-Tooth disease . [ 5 ] [ 6 ]


The COX6A1 gene, located on the q arm of  chromosome 12  in position 24.2, contains 3  exons  and is 2,653  base pairs  in length. [ 5 ]  The COX6A1 protein weighs 12 kDa and is composed of 109  amino acids . [ 7 ] [ 8 ]  The protein is a subunit of  Complex IV , a  heteromeric  complex consisting of 3 catalytic subunits encoded by  mitochondrial  genes and multiple structural subunits encoded by nuclear genes. This nuclear gene encodes polypeptide 1 (liver isoform) of subunit VIa, and polypeptide 1 is found in all non-muscle tissues. Polypeptide 2 (heart/muscle isoform) of subunit VIa is encoded by a different gene,  COX6A2 , and is present only in  striated muscles . These two polypeptides share 66% amino acid sequence identity. [ 5 ]


Cytochrome  c  oxidase (COX) is the terminal enzyme of the  mitochondrial  respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome  c  to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane to drive  ATP  synthesis via  protonmotive force .  The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex. [ 5 ]


Summary reaction:


A  mutation  leading to a 5 base pair deletion in the COX6A1 gene is associated with  Charcot-Marie-Tooth disease  (CMT). CMT is the most common inherited neuropathy and can result from mutations in over 30 different loci. Expression of COX6A1 is significantly reduced in affected individuals. [ 10 ]


The  Trans -activator of transcription protein  (Tat) of  human immunodeficiency virus  (HIV) inhibits cytochrome  c  oxidase (COX) activity in permeabilized mitochondria isolated from both mouse and human liver, heart, and brain samples. Rapid loss of  membrane potential  (ΔΨ m ) occurs with submicromolar doses of Tat, and cytochrome  c  is released from the mitochondria. [ 11 ]


Cytochrome c oxidase subunit 6B1  is an  enzyme  that in humans is encoded by the  COX6B1   gene . [ 4 ]  Cytochrome  c  oxidase 6B1 is a subunit of the cytochrome  c  oxidase complex, also known as  Complex IV , the last enzyme in the  mitochondrial   electron transport chain . Mutations of the COX6B1 gene are associated with severe infantile  encephalomyopathy  and mitochondrial complex IV deficiency (MT-C4D). [ 5 ]


The COX6B1 gene, located on the q arm of  chromosome 19  in position 13.1, contains 4  exons  and is 10,562  base pairs  in length. [ 5 ]  The COX6B1 protein weighs 10 kDa and is composed of 86 amino acids. [ 6 ] [ 7 ]  The protein is a subunit of  Complex IV , a heteromeric complex consisting of 3 catalytic subunits encoded by  mitochondrial  genes, and multiple structural subunits encoded by nuclear genes. [ 5 ]


Cytochrome c oxidase (COX), the terminal enzyme of the  mitochondrial respiratory chain , catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes subunit VIb. Three pseudogenes COX6BP-1, COX6BP-2 and COX6BP-3 have been found on chromosomes 7, 17 and 22q13.1-13.2, respectively. [ 5 ]


Mutations affecting the  COX6B1  gene are associated with mitochondrial complex IV deficiency (MT-C4D), a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated  myopathy  to severe multisystem disease affecting several tissues and organs. Features include  hypertrophic   cardiomyopathy ,  hepatomegaly  and  liver dysfunction ,  hypotonia ,  muscle weakness ,  exercise intolerance ,  developmental delay ,  delayed motor development , and  mental retardation . Some affected individuals manifest a fatal  hypertrophic cardiomyopathy  resulting in neonatal death. A subset of patients manifest  Leigh's syndrome . [ 9 ]  A  COX6B1  R20C  missense mutation  has been linked to complex IV deficiency with  encephalomyopathy ,  hydrocephalus , and hypertrophic cardiomyopathy. [ 10 ]


COX6B1 has been shown to have 548 binary  protein-protein interactions  including 547 co-complex interactions. [ 11 ]


Crystallin, lambda 1  is a  protein  that in  humans  is encoded by the CRYL1  gene .
 [ 1 ]


This article on a  gene  on human  chromosome 13  is a  stub . You can help Wikipedia by  expanding it .


A  cryptogene  is a  gene  that has had its  transcript  edited. [ 1 ]  This phenomenon is observed in various organisms, particularly in  Kinetoplastids  and  Myxomycetes , where the process plays a crucial role in  mitochondrial  gene expression.


Kinetoplastids , a group of protozoans including  Trypanosoma  and  Leishmania , possess an unusual genetic system in their  mitochondria .  This system is characterized by an elaborate network of circular DNA, organized into two distinct types of rings: maxicircles and minicircles.


Myxomycetes, a group of slime molds which includes species like  Physarum polycephalum , also exhibit cryptogenes in their mitochondria.  [ 3 ]


4HNI ,  4HOK


NM_001894 NM_152221


NM_013767 NM_001289898 NM_001289899 NM_001359862 NM_001359863


NP_001885 NP_689407


NP_001276827 NP_001276828 NP_038795 NP_001346791 NP_001346792


Casein kinase I isoform epsilon  is an  enzyme  that in humans is encoded by the  CSNK1E   gene . [ 5 ] [ 6 ]


The protein encoded by this gene is a  serine/threonine protein kinase  and a member of the  casein kinase I  protein family, whose members have been implicated in the control of  cytoplasmic  and  nuclear  processes, including  DNA replication  and  repair . The encoded protein is found in the cytoplasm as a monomer and can  phosphorylate  a variety of proteins, including itself. This protein has been shown to phosphorylate proteins of the Period family of  circadian rhythm  proteins. A  homolog  of this mammalian protein can be found in  Drosophila melanogaster . Known as  doubletime , this protein also plays a role in the phosphorylation of proteins involved in circadian rhythms. Two transcript variants encoding the same protein have been found for this gene. [ 7 ]


CSNK1E has been shown to  interact  with  PER1 [ 8 ]  and  AXIN1 . [ 9 ]


This article on a  gene  on human  chromosome 22  is a  stub . You can help Wikipedia by  expanding it .


CXorf49  is a  protein , which in  humans  is encoded by the  gene  chromosome X  open reading frame  49(CXorf49).


The CXorf49 gene has one alias CXorf49B. [ 1 ]  The recname A8MYA2 also refers to the protein coded by CXorf49 or CXorf49B. [ 2 ]


CXorf49 is located on the  X chromosome  at Xq13.1. It is 3912  base pairs  long and the gene sequence has 6  exons . [ 3 ]  CXorf49 has one protein coding  transcript. [ 4 ]


The protein has 514  amino acids  and a molecular mass of 54.4 kDa. [ 5 ]  The  isoelectric point  is 9.3. Compared to other human proteins CXorf49 is   glycine - and  proline -rich, but the protein has lower levels of  asparagine ,  isoleucine ,  tyrosine  and  threonine (Statistical Analysis of Protein Sequences, SAPS  [ 6 ] ).


The  domain of unknown function , DUF4641, is almost the entire protein. It is 433 amino acids long, from amino acid 80 until amino acid number 512. [ 7 ]  DUF4641 is a part of pfam15483. [ 8 ]  The domain is proline- and arginine-rich, but DUF4641 has lower levels of isoleucine, tyrosine and threonine compared to other proteins in human (Analysis of Protein Sequences, SAPS  [ 6 ] ). DUF4641 has an unusual spacing between  lysine  residues and positive charged amino acids (Analysis of Protein Sequences, SAPS  [ 6 ] ).


CXorf49 is predicted to have several post-translational sites. This include sites for N-acetyltransferase (NetAcet 1- [ 9 ] ), glycation of ε amino groups of lysines (NetGlycate 1.0 [ 10 ] ), mucin type GalNAc O-glycosylation  (NetOglyc 4.0 [ 11 ] ), phosphorylation (NetPhos 2.0 [ 12 ] ), sumoylation (SUMOplot Analysis Program [ 13 ] ) and O-ß-GlcNAc attachment(YinOYang WWW [ 14 ] ).


The CXorf49 protein has been predicted to be located in the  cell nucleus  (PSORT II  [ 15 ] ).


The  promoter  region of CXorf49  is located between base pair  71718051 and 71718785 on the minus strand of the X chromosome and it is 735 bp long (Genomatix’s ElDorado program [ 16 ] ). One of the most frequent  transcription factor  binding-sites in the promoter region are sites for Y-box binding factor.


Though expression of CXorf49 is very low in human cells, is it somewhat higher in  connective tissues ,  testis  and  uterus (NCBI-Unigene  [ 17 ] ).


The protein CXorf49 has not yet been shown to interact with other proteins (PSICQUIC [ 18 ] ).


CXorf49 is found to be one of the components of a small group of the  HL-60  cell  proteome  that were most prone to form  4-Hydroxy-2-nonenal (HNE) adducts, upon exposure to nontoxic (10 μM) HNE concentrations, along with heat shock 60 kDa protein 1. [ 19 ]


Using BLAST [ 20 ]  no orthologs for CXorf49 are found in single celled organisms, fungi or plants whose genomes have been sequenced. For multicellular organisms orthologs are found in mammals. The table below show a selection of the mammal orthologs. They are listed after time of divergence from human.


CXorf49 has developed from  aardvarks ,  to the human protein over 105.0 million years.


NM_028057 NM_001355133


NP_082333 NP_001342062


NADH-cytochrome b5 reductase 1  is an  enzyme  that in humans is encoded by the  CYB5R1   gene . [ 5 ] [ 6 ] [ 7 ]


The CYB5R1 gene is located on the  1st chromosome , with its specific location being 1q32.1. The gene contains 9  exons . [ 7 ]  CYB5R1 encodes a 34.1 kDa protein that is composed of 305  amino acids ; 56  peptides  have been observed through  mass spectrometry  data. [ 8 ] [ 9 ]


De novo  gene birth  is the process by which new  genes  evolve from  non-coding DNA . [ 1 ] [ 3 ]   De novo  genes represent a subset of novel genes, and may be protein-coding or instead act as RNA genes. [ 4 ]  The processes that govern  de novo  gene birth are not well understood, although several models exist that describe possible mechanisms by which  de novo  gene birth may occur.


Although  de novo  gene birth may have occurred at any point in an organism's evolutionary history, ancient  de novo  gene birth events are difficult to detect. Most studies of  de novo  genes to date have thus focused on young genes, typically taxonomically restricted genes (TRGs) that are present in a single species or lineage, including so-called  orphan genes , defined as genes that lack any identifiable homolog. It is important to note, however, that not all orphan genes arise  de novo , and instead may emerge through fairly well characterized mechanisms such as  gene duplication  (including retroposition) or  horizontal gene transfer  followed by sequence divergence, or by  gene fission/fusion . [ 5 ] [ 6 ]


Although  de novo  gene birth was once viewed as a highly unlikely occurrence, [ 7 ]  several unequivocal examples have now been described, [ 8 ]  and some researchers speculate that  de novo  gene birth could play a major role in evolutionary innovation, morphological specification, and adaptation, [ 9 ] [ 10 ]  probably promoted by their low level of  pleiotropy .


As early as the 1930s,  J. B. S. Haldane  and others suggested that copies of existing genes may lead to new genes with novel functions. [ 6 ]  In 1970,  Susumu Ohno  published the seminal text  Evolution by  Gene Duplication . [ 11 ]  For some time subsequently, the consensus view was that virtually all genes were derived from ancestral genes, [ 12 ]  with  François Jacob  famously remarking in a 1977 essay that "the probability that a functional protein would appear  de novo  by random association of amino acids is practically zero." [ 7 ]


In the same year, however, Pierre-Paul Grassé coined the term " overprinting " to describe the emergence of genes through the expression of alternative  open reading frames  (ORFs) that overlap preexisting genes. [ 13 ]  These new ORFs may be out of frame with or antisense to the preexisting gene. They may also be in frame with the existing ORF, creating a truncated version of the original gene, or represent 3’ extensions of an existing ORF into a nearby ORF. The first two types of overprinting may be thought of as a particular subtype of  de novo  gene birth; although overlapping with a previously coding region of the genome, the primary amino-acid sequence of the new protein is entirely novel and derived from a frame that did not previously contain a gene. The first examples of this phenomenon in  bacteriophages  were reported in a series of studies from 1976 to 1978, [ 14 ] [ 15 ] [ 16 ]  and since then numerous other examples have been identified in viruses, bacteria, and several eukaryotic species. [ 17 ] [ 18 ] [ 19 ] [ 20 ] [ 21 ] [ 22 ]


The phenomenon of exonization also represents a special case of  de novo  gene birth, in which, for example, often-repetitive intronic sequences acquire splice sites through mutation, leading to  de novo  exons. This was first described in 1994 in the context of  Alu  sequences found in the coding regions of primate mRNAs. [ 23 ]  Interestingly, such  de novo  exons are frequently found in minor splice variants, which may allow the evolutionary “testing” of novel sequences while retaining the functionality of the major splice variant(s). [ 24 ]


Still, it was thought by some that most or all eukaryotic proteins were constructed from a constrained pool of “starter type” exons. [ 25 ]  Using the sequence data available at the time, a 1991 review estimated the number of unique, ancestral eukaryotic exons to be < 60,000, [ 25 ]  while in 1992 a piece was published estimating that the vast majority of proteins belonged to no more than 1,000 families. [ 26 ]  Around the same time, however, the sequence of chromosome III of the budding yeast  Saccharomyces cerevisiae  was released, [ 27 ]  representing the first time an entire chromosome from any eukaryotic organism had been sequenced. Sequencing of the entire yeast nuclear genome was then completed by early 1996 through a massive, collaborative international effort. [ 28 ]  In his review of the yeast genome project,  Bernard Dujon  noted that the unexpected abundance of genes lacking any known homologs was perhaps the most striking finding of the entire project. [ 28 ]


In 2006 and 2007, a series of studies provided arguably the first documented examples of  de novo  gene birth that did not involve overprinting. [ 29 ] [ 30 ] [ 31 ]  These studies were conducted using the accessory gland transcriptomes of  Drosophila yakuba  and  Drosophila erecta  and they identified 20 putative lineage-restricted genes that appeared unlikely to have resulted from gene duplication. [ 31 ]  Levine and colleagues identified and confirmed five  de novo  candidate genes specific to  Drosophila melanogaster  and/or the closely related  Drosophila simulans  through a rigorous approach that combined bioinformatic and experimental techniques. [ 30 ]


Since these initial studies, many groups have identified specific cases of  de novo  gene birth events in diverse organisms. [ 32 ]  The first  de novo  gene identified in yeast,  BSC4  gene was identified in  S. cerevisiae  in 2008. This gene shows evidence of purifying selection, is expressed at both the mRNA and protein levels, and when deleted is synthetically lethal with two other yeast genes, all of which indicate a functional role for the  BSC4  gene product. [ 33 ]  Historically, one argument against the notion of widespread  de novo  gene birth is the evolved complexity of protein folding. Interestingly, Bsc4 was later shown to adopt a partially folded state that combines properties of native and non-native protein folding. [ 34 ]  In plants, the first  de novo  gene to be functionally characterized was  QQS , an  Arabidopsis thaliana  gene identified in 2009 that regulates carbon and nitrogen metabolism. [ 35 ]  The first functionally characterized  de novo  gene identified in mice, a noncoding RNA gene, was also described in 2009. [ 36 ]  In primates, a 2008 informatic analysis estimated that 15/270 primate orphan genes had been formed  de novo . [ 37 ]  A 2009 report identified the first three  de novo  human genes, one of which is a therapeutic target in chronic lymphocytic leukemia. [ 38 ]  Since this time, a plethora of genome-level studies have identified large numbers of orphan genes in many organisms, although the extent to which they arose  de novo , and the degree to which they can be deemed functional, remain debated.


There are two major approaches to the systematic identification of novel genes:  genomic phylostratigraphy [ 39 ]  and  synteny -based methods. [ 40 ]  Both approaches are widely used, individually or in a complementary fashion.


Genomic phylostratigraphy involves examining each gene in a focal, or reference, species and inferring the presence or absence of ancestral  homologs  through the use of the  BLAST  sequence alignment algorithms [ 41 ]  or related tools. Each gene in the focal species can be assigned an age (aka “conservation level” or “genomic phylostratum”) that is based on a predetermined phylogeny, with the age corresponding to the most distantly related species in which a homolog is detected. [ 39 ]  When a gene lacks any detectable homolog outside of its own genome, or close relatives, it is said to be a novel, taxonomically restricted or orphan gene.


Phylostratigraphy is limited by the set of closely related genomes that are available, and results are dependent on BLAST search criteria. [ 42 ]  In addition, it is often difficult to determine based on lack of observed sequence similarity whether a novel gene has emerged  de novo  or has diverged from an ancestral gene beyond recognition, for instance following a duplication event. This was pointed out by a study that simulated the evolution of genes of equal age and found that distant orthologs can be undetectable for rapidly evolving genes. [ 43 ]  On the other hand, when accounting for changes in the rate of evolution in young regions of genes, a phylostratigraphic approach was more accurate at assigning gene ages in simulated data. [ 44 ]  Subsequent studies using simulated evolution found that phylostratigraphy failed to detect an ortholog in the most distantly related species for 13.9% of  D. melanogaster  genes and 11.4% of  S. cerevisiae  genes. [ 45 ] [ 46 ]   However, a reanalysis of studies that used phylostratigraphy in yeast, fruit flies and humans found that even when accounting for such error rates and excluding difficult-to-stratify genes from the analyses, the qualitative conclusions were unaffected. [ 47 ]  The impact of phylostratigraphic bias on studies examining various features of  de novo  genes remains debated.


Synteny-based approaches use order and relative positioning of genes (or other features) to identify the potential ancestors of candidate  de novo  genes. [ 10 ] [ 42 ]  Syntenic alignments are anchored by conserved “markers.” Genes are the most common marker in defining syntenic blocks, although k-mers and exons are also used. [ 48 ] [ 40 ]  Confirmation that the syntenic region lacks coding potential in outgroup species allows a  de novo  origin to be asserted with higher confidence. [ 42 ]  The strongest possible evidence for  de novo  emergence is the inference of the specific "enabling" mutation(s) that created coding potential, typically through the analysis of smaller sequence regions, termed microsyntenic regions, of closely related species.


One challenge in applying synteny-based methods is that synteny can be difficult to detect across longer timescales. To address this, various optimization techniques have been created, such as using exons clustered irrespective of their specific order to define syntenic blocks [ 40 ]  or algorithms that use well-conserved genomic regions to expand microsyntenic blocks. [ 49 ]  There are also difficulties associated with applying synteny-based approaches to genome assemblies that are fragmented [ 50 ]  or in lineages with high rates of chromosomal rearrangements, as is common in insects. [ 51 ]  Synteny-based approaches can be applied to genome-wide surveys of  de novo  genes [ 37 ] [ 38 ] [ 52 ] [ 53 ] [ 54 ] [ 55 ] [ 56 ] [ 57 ]  and represent a promising area of algorithmic development for gene birth dating. Some have used synteny-based approaches in combination with similarity searches in an attempt to develop standardized, stringent pipelines [ 58 ]  that can be applied to any group of genomes in an attempt to address discrepancies in the various lists of  de novo  genes that have been generated.


Even when the evolutionary origin of a particular coding sequence has been established, there is still a lack of consensus about what constitutes a genuine  de novo  gene birth event. One reason for this is a lack of agreement on whether or not the entirety of the sequence must be non-genic in origin. For protein-coding  de novo  genes, it has been proposed that  de novo  genes be divided into subtypes based on the proportion of the ORF in question that was derived from a previously noncoding sequence. [ 42 ]  Furthermore, for  de novo  gene birth to occur, the sequence in question must be a gene which has led to a questioning of what constitutes a gene, with some models establishing a strict dichotomy between genic and non-genic sequences, and others proposing a more fluid continuum. [ 59 ]


All definitions of genes are linked to the notion of function, as it is generally agreed that a genuine gene should encode a functional product, be it RNA or protein. There are, however, different views of what constitutes function, depending whether a given sequence is assessed using genetic, biochemical, or evolutionary approaches. [ 42 ] [ 60 ] [ 61 ] [ 62 ]  The ambiguity of the concept of ‘function’ is especially problematic for the  de novo  gene birth field, where the objects of study are often rapidly evolving. [ 62 ]  To address these challenges, the Pittsburgh Model of Function deconstructs ‘function’ into five meanings to describe the different properties that are acquired by a locus undergoing  de novo  gene birth: Expression, Capacities, Interactions, Physiological Implications, and Evolutionary Implications. [ 62 ]


It is generally accepted that a genuine  de novo  gene is expressed in at least some context, [ 5 ]  allowing selection to operate, and many studies use evidence of expression as an inclusion criterion in defining  de novo  genes. The expression of sequences at the mRNA level may be confirmed individually through techniques such as  quantitative PCR , or globally through  RNA sequencing (RNA-seq) . Similarly, expression at the protein level can be determined with high confidence for individual proteins using techniques such as  mass spectrometry  or  western blotting , while  ribosome profiling  (Ribo-seq) provides a global survey of translation in a given sample. Ideally, to confirm a gene arose  de novo , a lack of expression of the syntenic region of outgroup species would also be demonstrated. [ 63 ]


Genetic approaches to detect a specific phenotype or change in fitness upon disruption of a particular sequence, are useful to infer function. [ 61 ]  Other experimental approaches, including screens for protein-protein and/or genetic interactions, may also be employed to confirm a biological effect for a particular  de novo  ORF.


Evolutionary approaches may be employed to infer the existence of a molecular function from computationally derived signatures of selection. In the case of TRGs, one common signature of selection is the ratio of nonsynonymous to synonymous substitutions ( dN/dS ratio ), calculated from different species from the same taxon. Similarly, in the case of species-specific genes, polymorphism data may be used to calculate a pN/pS ratio from different strains or populations of the focal species. Given that young, species-specific  de novo  genes lack deep conservation by definition, detecting statistically significant deviations from 1 can be difficult without an unrealistically large number of sequenced strains/populations. An example of this can be seen in  Mus musculus , where three very young  de novo  genes lack signatures of selection despite well-demonstrated physiological roles. [ 64 ]  For this reason, pN/pS approaches are often applied to groups of candidate genes, allowing researchers to infer that at least some of them are evolutionarily conserved, without being able to specify which. Other signatures of selection, such as the degree of nucleotide divergence within syntenic regions, conservation of ORF boundaries, or for protein-coding genes, a coding score based on nucleotide hexamer frequencies, have instead been employed. [ 65 ] [ 66 ]


Frequency and number estimates of  de novo  genes in various lineages vary widely and are highly dependent on methodology. Studies may identify  de novo  genes by phylostratigraphy/BLAST-based methods alone, or may employ a combination of computational techniques, and may or may not assess experimental evidence for expression and/or biological role. [ 10 ]  Furthermore, genome-scale analyses may consider all or most ORFs in the genome, [ 59 ]  or may instead limit their analysis to previously annotated genes.


The  D. melanogaster  lineage is illustrative of these differing approaches. An early survey using a combination of BLAST searches performed on cDNA sequences along with manual searches and synteny information identified 72 new genes specific to  D. melanogaster  and 59 new genes specific to three of the four species in the  D. melanogaster  species complex. This report found that only 2/72 (~2.8%) of  D. melanogaster -specific new genes and 7/59 (~11.9%) of new genes specific to the species complex were derived  de novo , [ 56 ]  with the remainder arising via duplication/retroposition. Similarly, an analysis of 195 young (<35 million years old)  D. melanogaster  genes identified from syntenic alignments found that only 16 had arisen  de novo . [ 54 ]  In contrast, an analysis focused on transcriptomic data from the testes of six  D. melanogaster  strains identified 106 fixed and 142 segregating  de novo  genes. [ 55 ]  For many of these, ancestral ORFs were identified but were not expressed. A newer study found that up to 39 % of orphan genes in the  Drosophila  clade may have emerged  de novo , as they overlap with non-coding regions of the genome. [ 67 ]  Highlighting the differences between inter- and intra-species comparisons, a study in natural  Saccharomyces paradoxus  populations found that the number of  de novo  polypeptides identified more than doubled when considering intra-species diversity. [ 68 ]  In primates, one early study identified 270 orphan genes (unique to humans, chimpanzees, and macaques), of which 15 were thought to have originated  de novo . [ 37 ]  Later reports identified many more  de novo  genes in humans alone that are supported by transcriptional and proteomic evidence. [ 57 ] [ 69 ]  Studies in other lineages/organisms have also reached different conclusions with respect to the number of  de novo  genes present in each organism, as well as the specific sets of genes identified. A sample of these large-scale studies is described in the table below.


Generally speaking, it remains debated whether duplication and divergence or  de novo  gene birth represent the dominant mechanism for the emergence of new genes, [ 54 ] [ 56 ] [ 59 ] [ 70 ] [ 71 ] [ 72 ]  in part because  de novo  genes are likely to both emerge and be lost more frequently than other young genes. In a study on the origin of orphan genes in 3 different eukaryotic lineages, authors found that on average only around 30% of orphan genes can be explained by sequence divergence. [ 72 ]


It is important to distinguish between the frequency of  de novo  gene birth and the number of  de novo  genes in a given lineage. If  de novo  gene birth is frequent, it might be expected that genomes would tend to grow in their gene content over time; however, the gene content of genomes is usually relatively stable. [ 10 ]  This implies that a frequent gene death process must balance  de novo  gene birth, and indeed,  de novo  genes are distinguished by their rapid turnover relative to established genes. In support of this notion, recently emerged  Drosophila  genes are much more likely to be lost, primarily through  pseudogenization , with the youngest orphans being lost at the highest rate; [ 73 ]  this is despite the fact that some  Drosophila  orphan genes have been shown to rapidly become essential. [ 54 ]  A similar trend of frequent loss among young gene families was observed in the nematode genus  Pristionchus . [ 74 ]  Similarly, an analysis of five mammalian transcriptomes found that most ORFs in mice were either very old or species specific, implying frequent birth and death of  de novo  transcripts. [ 71 ]  A comparable trend could be shown by further analyses of six primate transcriptomes. [ 69 ]  In wild  S. paradoxus  populations,  de novo  ORFs emerge and are lost at similar rates. [ 68 ]  Nevertheless, there remains a positive correlation between the number of species-specific genes in a genome and the evolutionary distance from its most recent ancestor. [ 75 ] [ 67 ]  A rapid gain and loss of  de novo  genes was also found on a population level by analyzing nine natural three-spined stickleback populations. [ 76 ]  In addition to the birth and death of  de novo  genes at the level of the ORF, mutational and other processes also subject genomes to constant “transcriptional turnover”. One study in murines found that while all regions of the ancestral genome were transcribed at some point in at least one descendant, the portion of the genome under active transcription in a given strain or subspecies is subject to rapid change. [ 77 ]  The transcriptional turnover of noncoding RNA genes is particularly fast compared to coding genes. [ 78 ]


de novo  origin


RNA i  knockdown experiments in male flies


cerevisiae


Recently emerged  de novo  genes differ from established genes in a number of ways. Across a broad range of species, young and/or taxonomically restricted genes have been reported to be shorter in length than established genes, more positively charged, faster evolving, [ 88 ]  and to be less expressed. [ 37 ] [ 59 ] [ 73 ] [ 74 ] [ 89 ] [ 90 ] [ 91 ] [ 92 ] [ 93 ] [ 94 ] [ 95 ] [ 96 ] [ 71 ] [ 69 ] [ 67 ] [ 76 ] [ excessive citations ]  Although these trends could be a result of homology detection bias, a reanalysis of several studies that accounted for this bias found that the qualitative conclusions reached were unaffected. [ 47 ]  Another feature includes the tendency for young genes to have their hydrophobic amino acids more clustered near one another along the primary sequence. [ 97 ] [ 98 ]


The expression of young genes has also been found to be more tissue- or condition-specific than that of established genes. [ 29 ] [ 31 ] [ 37 ] [ 55 ] [ 57 ] [ 59 ] [ 94 ] [ 99 ] [ 100 ] [ 101 ] [ 67 ] [ 76 ]  In particular, relatively high expression of  de novo  genes was observed in male reproductive tissues in  Drosophila , stickleback, mice, and humans, and, in the human brain. [ 57 ] [ 102 ] [ 67 ] [ 76 ]  In animals with adaptive immune systems, higher expression in the brain and testes may be a function of the immune-privileged nature of these tissues. An analysis in mice found specific expression of intergenic transcripts in the thymus and spleen (in addition to the brain and testes). It has been proposed that in vertebrates  de novo  transcripts must first be expressed in tissues lacking immune cells before they can be expressed in tissues that have immune surveillance. [ 101 ]


For sequence evolution, dN/dS analysis studies often indicate that de novo genes evolve at a higher rate compared to other genes. [ 103 ] [ 88 ]  For expression evolution and structural evolution, quantitative studies across different evolutionary ages or phylostratigraphic branches are very few.


Its also of interest to compare features of recently emerged  de novo  genes to the pool of non-genic ORFs from which they emerge. Theoretical modeling has shown that such differences are the product both of selection for features that increase the likelihood of functionalization, and of neutral evolutionary forces that influence allelic turnover. [ 104 ]  Experiments in  S. cerevisiae  showed that predicted transmembrane domains were strongly associated with beneficial fitness effects when young ORFs were overexpressed, but not when established (older) ORFs were overexpressed. [ 105 ]  Experiments in  E. coli  showed that random peptides tended to have more benign effects when they were enriched for amino acids that were small, and that promoted intrinsic structural disorder. [ 106 ]


Features of  de novo  genes can depend on the species or lineage being examined. This appears to partly be a result of varying  GC content  in genomes and that young genes bear more similarity to non-genic sequences from the genome in which they arose than do established genes. [ 107 ]  Features in the resulting protein, such as the percentage of transmembrane residues and the relative frequency of various predicted  secondary structural features  show a strong GC dependency in orphan genes, whereas in more ancient genes these features are only weakly influenced by GC content. [ 107 ]


The relationship between gene age and the amount of predicted  intrinsic structural disorder  (ISD) in the encoded proteins has been subject to considerable debate. It has been claimed that ISD is also a lineage-dependent feature, exemplified by the fact that in organisms with relatively high GC content, ranging from  D. melanogaster  to the parasite  Leishmania major , young genes have high ISD, [ 108 ] [ 109 ]  while in a low GC genome such as budding yeast, several studies have shown that young genes have low ISD. [ 59 ] [ 89 ] [ 96 ] [ 107 ]  However, a study that excluded young genes with dubious evidence for functionality, defined in binary terms as being under selection for gene retention, found that the remaining young yeast genes have high ISD, suggesting that the yeast result may be due to contamination of the set of young genes with ORFs that do not meet this definition, and hence are more likely to have properties that reflect GC content and other non-genic features of the genome. [ 110 ]  Beyond the very youngest orphans, this study found that ISD tends to decrease with increasing gene age, and that this is primarily due to amino acid composition rather than GC content. [ 110 ]  Within shorter time scales, using  de novo  genes that have the most validation suggests that younger genes are more disordered in  Lachancea , but less disordered in  Saccharomyces . [ 96 ]  Intrinsic structural disorder and aggregation propensity did not show significant differences with age in some studies of mammals  [ 71 ]  and primates, [ 69 ]  but did in other studies of mammals. [ 110 ]  One large study of the entire Pfam protein domain database showed enrichment of younger protein domain for disorder-promoting amino acids across animals, but enrichment on the basis of amino acid availability in plants. [ 98 ]


An examination of  de novo  genes in  A. thaliana  found that they are both  hypermethylated  and generally depleted of  histone  modifications. [ 53 ]  In agreement with either the proto-gene model or contamination with non-genes, methylation levels of  de novo  genes were intermediate between established genes and intergenic regions. The methylation patterns of these  de novo  genes are stably inherited, and methylation levels were highest, and most similar to established genes, in  de novo  genes with verified protein-coding ability. [ 53 ]  In the pathogenic fungus  Magnaporthe oryzae , less conserved genes tend to have  methylation  patterns associated with low levels of transcription. [ 111 ]  A study in yeasts also found that  de novo  genes are enriched at  recombination hotspots , which tend to be nucleosome-free regions. [ 96 ]


In  Pristionchus pacificus , orphan genes with confirmed expression display chromatin states that differ from those of similarly expressed established genes. [ 95 ]  Orphan gene start sites have epigenetic signatures that are characteristic of enhancers, in contrast to conserved genes that exhibit classical promoters. [ 95 ]  Many unexpressed orphan genes are decorated with repressive histone modifications, while a lack of such modifications facilitates transcription of an expressed subset of orphans, supporting the notion that open chromatin promotes the formation of novel genes. [ 95 ]


De novo proteins typically exhibit less well-defined secondary and three-dimensional structures, often lacking rigid folding but having extensive disordered regions. [ 103 ] [ 110 ]  Quantitative analyses are still lacking on the evolution of secondary structural elements and tertiary structures over time. As structure is usually more conserved than sequence, comparing structures between orthologs could provide deeper insides into  de novo  gene emergence and evolution and help to confirm these genes as true  de novo  genes. [ 112 ]  Nevertheless, so far only very few  de novo  proteins have been structurally and functionally characterized, especially due to problems with protein purification and subsequent stability. Progresses have been made using different purification tags, cell types and chaperones. [ 113 ]


The ‘antifreeze glycoprotein’ (AFGP) in Arctic codfishes prevents their blood from freezing in arctic waters. [ 84 ] [ 83 ]  Bsc4, a short non-essential  de novo  protein in yeast, [ 33 ]  has been shown to be built mainly by β-sheets and has a hydrophobic core. [ 34 ]  It is associated to DNA repair under nutrient-deficient conditions. [ 114 ]  The  Drosophila   de novo  protein Goddard has been characterized for the first time in 2017. Knockdown  Drosophila melanogaster  male flies were not able to produce sperm. [ 80 ]  Recently, it could be shown that this lack was due to failure of individualization of elongated spermatids. By using computational phylogenomic and structure predictions, experimental structural analyses, and cell biological assays, it was proposed that half of Goddard's structure is disordered and the other half is composed by alpha-helical amino acids. These analyses also indicated that Goddard's orthologs show similar results. Goddard's structure therefore appears to have been mainly conserved since its emergence. [ 81 ]


With the development of technologies such as RNA-seq and Ribo-seq, eukaryotic genomes are now known to be pervasively transcribed [ 115 ] [ 116 ] [ 117 ] [ 118 ]  and translated. [ 119 ]  Many ORFs that are either unannotated, or annotated as  long non-coding RNAs  (lncRNAs), are translated at some level, either in a condition or tissue-specific manner. [ 59 ] [ 119 ] [ 120 ] [ 121 ] [ 122 ] [ 123 ]  Though infrequent, these translation events expose non-genic sequence to selection. This pervasive expression forms the basis for several models describing  de novo  gene birth.


It has been speculated that the epigenetic landscape of  de novo  genes in the early stages of formation may be particularly variable between and among populations, resulting in variable gene expression thereby allowing young genes to explore the “expression landscape.” [ 124 ]  The  QQS  gene in  A. thaliana  is one example of this phenomenon; its expression is negatively regulated by DNA methylation that, while heritable for several generations, varies widely in its levels both among natural accessions and within wild populations. [ 124 ]  Epigenetics are also largely responsible for the permissive transcriptional environment in the testes, particularly through the incorporation into nucleosomes of non-canonical histone variants that are replaced by histone-like  protamines  during spermatogenesis. [ 125 ]


Analysis of the fold potential diversity shows that the majority of the amino acid sequences encoded by the intergenic ORFs of  S. cerevisiae  are predicted to be foldable. [ 126 ]  More importantly,  these amino acid sequences with folding potential can serve as elementary building blocks for de novo genes or integrate into pre-existing genes. [ 126 ]


For birth of a  de novo  protein-coding gene to occur, a non-genic sequence must both be transcribed and acquire an ORF before becoming translated. These events could occur in either order, and there is evidence supporting both an “ORF first” and a “transcription first” model. [ 5 ] [ 127 ]  An analysis of  de novo  genes that are segregating in  D. melanogaster  found that sequences that are transcribed had similar coding potential to the orthologous sequences from lines lacking evidence of transcription. [ 55 ]  This finding supports the notion that many ORFs can exist prior to being transcribed. The antifreeze glycoprotein gene  AFGP , which emerged  de novo  in Arctic codfishes, provides a more definitive example in which the  de novo  emergence of the ORF was shown to precede the promoter region. [ 83 ]  Furthermore, putatively non-genic ORFs long enough to encode functional peptides are numerous in eukaryotic genomes, and expected to occur at high frequency by chance. [ 55 ] [ 59 ]  Through tracing the evolution history of ORF sequences and transcription activation of human  de novo  genes, a study showed that some ORFs were ready to confer biological significance upon their birth. [ 127 ]  At the same time, transcription of eukaryotic genomes is far more extensive than previously thought, and there are documented examples of genomic regions that were transcribed prior to the appearance of an ORF that became a  de novo  gene. [ 79 ]  The proportion of  de novo  genes that are protein-coding is unknown, but the appearance of “transcription first” has led some to posit that protein-coding  de novo  genes may first exist as RNA gene intermediates. The case of bifunctional RNAs, which are both translated and function as RNA genes, shows that such a mechanism is plausible. [ 128 ]


The two events may occur simultaneously when chromosomal rearrangement is the event that precipitates gene birth. [ 129 ]


Several theoretical models and possible mechanisms of  de novo  gene birth have been described. The models are generally not mutually exclusive, and it is possible that multiple mechanisms may give rise to  de novo  genes. [ 42 ]  An example is the type III antifreeze protein gene, which originates from an old sialic acid synthase ( SAS ) gene, in an Antarctic zoarcid fish.


An early case study of  de novo  gene birth, which identified five  de novo  genes in  D. melanogaster , noted preferential expression of these genes in the testes, [ 30 ]  and several additional  de novo  genes were identified using transcriptomic data derived from the testes and male accessory glands of  D. yakuba  and  D. erecta . [ 29 ] [ 31 ]  This is in agreement with other studies that showed there is rapid evolution of genes related to reproduction across a range of lineages, [ 130 ] [ 131 ] [ 132 ]  suggesting that sexual selection may play a key role in adaptive evolution and  de novo  gene birth. A subsequent large-scale analysis of six  D. melanogaster  strains identified 248 testis-expressed  de novo  genes, of which ~57% were not fixed. [ 55 ]  A recent study on twelve  Drosophila  species additionally identified a higher proportion of  de novo  genes with testis-biased expression compared to annotated proteome. [ 67 ]  It has been suggested that the large number of  de novo  genes with male-specific expression identified in  Drosophila  is likely due to the fact that such genes are preferentially retained relative to other  de novo  genes, for reasons that are not entirely clear. [ 73 ]  Interestingly, two putative  de novo  genes in  Drosophila  ( Goddard  and  Saturn ) were shown to be required for normal male fertility. [ 80 ] [ 81 ]  A genetic screen of over 40 putative de novo genes with testis-enriched expression in  Drosophila melanogaster  revealed that one of the de novo genes,  atlas , was required for proper chromatin condensation during the final stages of spermatogenesis in male.  atlas  evolved from the fusion of a protein-coding gene that arose at the base of  Drosophila  genus and a conserved non-coding RNA. [ 133 ]  Comparative analysis of the transcriptomes of testis and accessory glands, a somatic tissue of males that is important for fertility, of  D. melanogaster  suggests that de novo genes make greater contribution to the transcriptomic complexity of testis as compared to accessory glands. [ 134 ]  Single-cell RNA-seq of  D. melanogaster  testis revealed that the expression pattern of de novo genes was biased toward early spermatogenesis. [ 135 ]


In humans, a study that identified 60 human-specific  de novo  genes found that their average expression, as measured by RNA-seq, was highest in the testes. [ 57 ]  Another study looking at mammalian-specific genes more generally also found enriched expression in the testes. [ 136 ]  Transcription in mammalian testes is thought to be particularly promiscuous, due in part to elevated expression of the transcription machinery [ 137 ] [ 138 ]  and an open chromatin environment. [ 139 ]  Along with the immune-privileged nature of the testes, this promiscuous transcription is thought to create the ideal conditions for the expression of non-genic sequences required for  de novo  gene birth. Testes-specific expression seems to be a general feature of all novel genes, as an analysis of  Drosophila  and vertebrate species found that young genes showed testes-biased expression regardless of their mechanism of origination. [ 99 ]


The preadaptation model of  de novo  gene birth uses mathematical modeling to show that when sequences that are normally hidden are exposed to weak or shielded selection, the resulting pool of “cryptic” sequences (i.e. proto-genes) can be purged of “self-evidently deleterious” variants, such as those prone to lead to protein aggregation, and thus enriched in potential adaptations relative to a completely non-expressed and unpurged set of sequences. [ 140 ]  This revealing and purging of cryptic deleterious non-genic sequences is a byproduct of pervasive transcription and translation of intergenic sequences, and is expected to facilitate the birth of functional  de novo  protein-coding genes. [ 122 ]  This is because by eliminating the most deleterious variants, what is left is, by a process of elimination, more likely to be adaptive than expected from random sequences. Using the evolutionary definition of function (i.e. that a gene is by definition under purifying selection against loss), the preadaptation model assumes that “gene birth is a sudden transition to functionality” [ 110 ]  that occurs as soon as an ORF acquires a net beneficial effect. In order to avoid being deleterious, newborn genes are expected to display exaggerated versions of genic features associated with the avoidance of harm. This is in contrast to the proto-gene model, which expects newborn genes to have features intermediate between old genes and non-genes. [ 110 ]


The mathematics of the preadaptation model assume that the distribution of fitness effects is bimodal, with new sequences of mutations tending to break something or tinker, but rarely in between. [ 140 ] [ 141 ]  Following this logic, populations may either evolve local solutions, in which selection operates on each individual locus and a relatively high error rate is maintained, or a global solution with a low error rate which permits the accumulation of deleterious cryptic sequences. [ 140 ]   De novo  gene birth is thought to be favored in populations that evolve local solutions, as the relatively high error rate will result in a pool of cryptic variation that is “preadapted” through the purging of deleterious sequences. Local solutions are more likely in populations with a high  effective population size .