ectodysplasin A receptor

{{Short description|Protein-coding gene in the species Homo sapiens}}

Ectodysplasin A receptor (EDAR) is a protein that in humans is encoded by the EDAR gene. EDAR is a cell surface receptor for ectodysplasin A which plays an important role in the development of ectodermal tissues such as the skin.{{cite journal | vauthors = Monreal AW, Ferguson BM, Headon DJ, Street SL, Overbeek PA, Zonana J | title = Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia | journal = Nature Genetics | volume = 22 | issue = 4 | pages = 366–9 | date = August 1999 | pmid = 10431241 | doi = 10.1038/11937 | s2cid = 11348633 }}{{cite journal | vauthors = Aswegan AL, Josephson KD, Mowbray R, Pauli RM, Spritz RA, Williams MS | title = Autosomal dominant hypohidrotic ectodermal dysplasia in a large family | journal = American Journal of Medical Genetics | volume = 72 | issue = 4 | pages = 462–7 | date = November 1997 | pmid = 9375732 | doi = 10.1002/(SICI)1096-8628(19971112)72:4<462::AID-AJMG17>3.0.CO;2-P }}{{cite web | title = Entrez Gene: EDAR ectodysplasin A receptor| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10913 }} It is structurally related to members of the TNF receptor superfamily.{{OMIM|604095}}

Function

EDAR and other genes provide instructions for making proteins that work together during embryonic development. These proteins form part of a signaling pathway that is critical for the interaction between two cell layers, the ectoderm and the mesoderm. In the early embryo, these cell layers form the basis for many of the body's organs and tissues. Ectoderm-mesoderm interactions are essential for the proper formation of several structures that arise from the ectoderm, including the skin, hair, nails, teeth, and sweat glands.

Clinical significance

Mutations in this gene have been associated with hypohidrotic ectodermal dysplasia, a disorder characterized by a lower density of sweat glands.

Derived EDAR allele

A derived G-allele point mutation (SNP) with pleiotropic effects in EDAR, 370A or rs3827760, is found in ancient and modern East Asians, North Asians, Southeast Asians, Nepalese, and Native Americans but not common in African or European populations. Experimental research in mice has linked the derived allele to a number of traits, including greater hair shaft diameter, more numerous sweat glands, smaller mammary fat pad, and increased mammary gland density.{{cite journal | vauthors = Kamberov YG, Wang S, Tan J, Gerbault P, Wark A, Tan L, Yang Y, Li S, Tang K, Chen H, Powell A, Itan Y, Fuller D, Lohmueller J, Mao J, Schachar A, Paymer M, Hostetter E, Byrne E, Burnett M, McMahon AP, Thomas MG, Lieberman DE, Jin L, Tabin CJ, Morgan BA, Sabeti PC | display-authors = 6 | title = Modeling recent human evolution in mice by expression of a selected EDAR variant | journal = Cell | volume = 152 | issue = 4 | pages = 691–702 | date = February 2013 | pmid = 23415220 | pmc = 3575602 | doi = 10.1016/j.cell.2013.01.016 }} A 2008 study stated that EDAR is a genetic determinant for hair thickness, and also contributed to variations in hair thickness among Asian populations.{{Cite journal |last=Fujimoto |first=Akihiro |last2=Ohashi |first2=Jun |last3=Nishida |first3=Nao |last4=Miyagawa |first4=Taku |display-authors=3 |date=2008 |title=A replication study confirmed the EDAR gene to be a major contributor to population differentiation regarding head hair thickness in Asia |url=https://pubmed.ncbi.nlm.nih.gov/18704500/ |journal=Human Genetics |volume=124 |issue=2 |pages=179-185 |via=NCBI}} Derived variants of EDAR are associated with multiple facial and dental characteristics, such as shovel-shaped incisors.{{cite journal |vauthors=Park JH, Yamaguchi T, Watanabe C, Kawaguchi A, Haneji K, Takeda M, Kim YI, Tomoyasu Y, Watanabe M, Oota H, Hanihara T, Ishida H, Maki K, Park SB, Kimura R |date=August 2012 |title=Effects of an Asian-specific nonsynonymous EDAR variant on multiple dental traits |journal=Journal of Human Genetics |volume=57 |issue=8 |pages=508–14 |doi=10.1038/jhg.2012.60 |pmid=22648185 |doi-access=free}}{{cite journal |vauthors=Tan J, Peng Q, Li J, Guan Y, Zhang L, Jiao Y, Yang Y, Wang S, Jin L |date=May 2014 |title=Characteristics of dental morphology in the Xinjiang Uyghurs and correlation with the EDARV370A variant |journal=Science China Life Sciences |volume=57 |issue=5 |pages=510–8 |doi=10.1007/s11427-014-4654-x |pmid=24752358 |doi-access=free}}{{cite journal |last1=Adhikari |first1=Kaustubh |last2=Fuentes-Guajardo |first2=Macarena |last3=Quinto-Sánchez |last4=Mendoza-Revilla |last5=Camilo Chacón-Duque |date=2016 |title=A genome-wide association scan implicates DCHS2, RUNX2, GLI3, PAX1 and EDAR in human facial variation |journal=Nature Communications |language=en |volume=7 |issue=1 |pages=11616 |bibcode=2016NatCo...711616A |doi=10.1038/ncomms11616 |issn=2041-1723 |pmc=4874031 |pmid=27193062}}{{cite journal |last1=Wang |first1=Chuan-Chao |last2=Yeh |first2=Hui-Yuan |last3=Popov |first3=Alexander N. |last4=Zhang |first4=Hu-Qin |last5=Matsumura |first5=Hirofumi |last6=Sirak |first6=Kendra |last7=Cheronet |first7=Olivia |last8=Kovalev |first8=Alexey |last9=Rohland |first9=Nadin |last10=Kim |first10=Alexander M. |last11=Mallick |first11=Swapan |last12=Bernardos |first12=Rebecca |last13=Tumen |first13=Dashtseveg |last14=Zhao |first14=Jing |last15=Liu |first15=Yi-Chang |date=March 2021 |title=Genomic insights into the formation of human populations in East Asia |journal=Nature |language=en |volume=591 |issue=7850 |pages=413–419 |bibcode=2021Natur.591..413W |doi=10.1038/s41586-021-03336-2 |issn=1476-4687 |pmc=7993749 |pmid=33618348 |last16=Liu |first16=Jiun-Yu |last17=Mah |first17=Matthew |last18=Wang |first18=Ke |last19=Zhang |first19=Zhao |last20=Adamski |first20=Nicole |last21=Broomandkhoshbacht |first21=Nasreen |last22=Callan |first22=Kimberly |last23=Candilio |first23=Francesca |last24=Carlson |first24=Kellie Sara Duffett |last25=Culleton |first25=Brendan J. |last26=Eccles |first26=Laurie |last27=Freilich |first27=Suzanne |last28=Keating |first28=Denise |last29=Lawson |first29=Ann Marie |last30=Mandl |first30=Kirsten |last31=Michel |first31=Megan |last32=Oppenheimer |first32=Jonas |last33=Özdoğan |first33=Kadir Toykan |last34=Stewardson |first34=Kristin |last35=Wen |first35=Shaoqing |last36=Yan |first36=Shi |last37=Zalzala |first37=Fatma |last38=Chuang |first38=Richard |last39=Huang |first39=Ching-Jung |last40=Looh |first40=Hana |last41=Shiung |first41=Chung-Ching |last42=Nikitin |first42=Yuri G. |last43=Tabarev |first43=Andrei V. |last44=Tishkin |first44=Alexey A. |last45=Lin |first45=Song |last46=Sun |first46=Zhou-Yong |last47=Wu |first47=Xiao-Ming |last48=Yang |first48=Tie-Lin |last49=Hu |first49=Xi |last50=Chen |first50=Liang |last51=Du |first51=Hua |last52=Bayarsaikhan |first52=Jamsranjav |last53=Mijiddorj |first53=Enkhbayar |last54=Erdenebaatar |first54=Diimaajav |last55=Iderkhangai |first55=Tumur-Ochir |last56=Myagmar |first56=Erdene |last57=Kanzawa-Kiriyama |first57=Hideaki |last58=Nishino |first58=Masato |last59=Shinoda |first59=Ken-ichi |last60=Shubina |first60=Olga A. |last61=Guo |first61=Jianxin |last62=Cai |first62=Wangwei |last63=Deng |first63=Qiongying |last64=Kang |first64=Longli |last65=Li |first65=Dawei |last66=Li |first66=Dongna |last67=Lin |first67=Rong |last68=Shrestha |first68=Rukesh |last69=Wang |first69=Ling-Xiang |last70=Wei |first70=Lanhai |last71=Xie |first71=Guangmao |last72=Yao |first72=Hongbing |last73=Zhang |first73=Manfei |last74=He |first74=Guanglin |last75=Yang |first75=Xiaomin |last76=Hu |first76=Rong |last77=Robbeets |first77=Martine |last78=Schiffels |first78=Stephan |last79=Kennett |first79=Douglas J. |last80=Jin |first80=Li |last81=Li |first81=Hui |last82=Krause |first82=Johannes |last83=Pinhasi |first83=Ron |last84=Reich |first84=David}} This mutation is also implicated in ear morphology differences and reduced chin protrusion.{{cite journal |display-authors=6 |vauthors=Adhikari K, Fuentes-Guajardo M, Quinto-Sánchez M, Mendoza-Revilla J, Camilo Chacón-Duque J, Acuña-Alonzo V, Jaramillo C, Arias W, Lozano RB, Pérez GM, Gómez-Valdés J, Villamil-Ramírez H, Hunemeier T, Ramallo V, Silva de Cerqueira CC, Hurtado M, Villegas V, Granja V, Gallo C, Poletti G, Schuler-Faccini L, Salzano FM, Bortolini MC, Canizales-Quinteros S, Cheeseman M, Rosique J, Bedoya G, Rothhammer F, Headon D, González-José R, Balding D, Ruiz-Linares A |date=May 2016 |title=A genome-wide association scan implicates DCHS2, RUNX2, GLI3, PAX1 and EDAR in human facial variation |journal=Nature Communications |volume=7 |pages=11616 |bibcode=2016NatCo...711616A |doi=10.1038/ncomms11616 |pmc=4874031 |pmid=27193062}}

A 2013 study suggested that the EDAR variant (370A) arose about 35,000 years ago in central China, a period during which the region was then quite warm and humid.{{Cite web |title=EDAR gene: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/gene/edar/ |access-date=2021-10-18 |website=medlineplus.gov |language=en}} A subsequent study from 2021, based on ancient DNA samples, has suggested that the derived variant became dominant among Ancient Northern East Asians shortly after the Last Glacial Maximum in Northeast Asia, around 19,000 years ago. Ancient remains from Northern East Asia, such as the Tianyuan Man (40,000 years old) and the AR33K (33,000 years old) specimen lacked the derived EDAR allele, while ancient East Asian remains after the LGM carry the derived EDAR allele.{{Cite journal |last1=Mao |first1=Xiaowei |last2=Zhang |first2=Hucai |last3=Qiao |first3=Shiyu |last4=Liu |first4=Yichen |last5=Chang |first5=Fengqin |last6=Xie |first6=Ping |last7=Zhang |first7=Ming |last8=Wang |first8=Tianyi |last9=Li |first9=Mian |last10=Cao |first10=Peng |last11=Yang |first11=Ruowei |last12=Liu |first12=Feng |last13=Dai |first13=Qingyan |last14=Feng |first14=Xiaotian |last15=Ping |first15=Wanjing |date=2021-06-10 |title=The deep population history of northern East Asia from the Late Pleistocene to the Holocene |journal=Cell |language=en |volume=184 |issue=12 |pages=3256–3266.e13 |doi=10.1016/j.cell.2021.04.040 |pmid=34048699 |issn=0092-8674|doi-access=free }}{{cite journal |last1=Zhang |first1=Xiaoming |last2=Ji |first2=Xueping |last3=Li |first3=Chunmei |last4=Yang |first4=Tingyu |last5=Huang |first5=Jiahui |last6=Zhao |first6=Yinhui |last7=Wu |first7=Yun |last8=Ma |first8=Shiwu |last9=Pang |first9=Yuhong |last10=Huang |first10=Yanyi |last11=He |first11=Yaoxi |last12=Su |first12=Bing |title=A Late Pleistocene human genome from Southwest China |journal=Current Biology |date=25 July 2022 |volume=32 |issue=14 |pages=3095–3109.e5 |doi=10.1016/j.cub.2022.06.016 |pmid=35839766 |s2cid=250502011 |language=en |issn=0960-9822|doi-access=free |bibcode=2022CBio...32E3095Z }}

It has been hypothesized that natural selection favored this allele during the last ice age in a population of people living in isolation in Beringia, as it may play a role in the synthesis of Vitamin D-rich breast milk in dark environments.{{cite news |last=Lozovschi |first=Alexandra |date=24 April 2018 |title=Ancient Teeth Reveal Breastfeeding-Related Gene Helped Early Americans Survive The Ice Age [Study] |url=https://www.inquisitr.com/4876126/ancient-teeth-reveal-breastfeeding-related-gene-helped-early-americans-survive-the-ice-age-study |access-date=25 April 2018 |work=Inquisitr}}{{cite news |author=Nicholas Wade |date=February 14, 2013 |title=East Asian Physical Traits Linked to 35,000-Year-Old Mutation |url=https://www.nytimes.com/2013/02/15/science/studying-recent-human-evolution-at-the-genetic-level.html |access-date=February 15, 2013 |newspaper=The New York Times}}{{cite journal |display-authors=6 |vauthors=Hlusko LJ, Carlson JP, Chaplin G, Elias SA, Hoffecker JF, Huffman M, Jablonski NG, Monson TA, O'Rourke DH, Pilloud MA, Scott GR |date=May 2018 |title=Environmental selection during the last ice age on the mother-to-infant transmission of vitamin D and fatty acids through breast milk |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=115 |issue=19 |pages=E4426–E4432 |bibcode=2018PNAS..115E4426H |doi=10.1073/pnas.1711788115 |pmc=5948952 |pmid=29686092 |doi-access=free}} One study suggested that because the EDAR mutation arose in a cool and dry environment, it may have been adaptive by increasing skin lubrication, thus reducing dryness in exposed facial structures.{{cite journal |last1=Chang |first1=Shie Hong |last2=Jobling |first2=Stephanie |last3=Brennan |first3=Keith |last4=Headon |first4=Denis J. |date=26 October 2009 |title=Enhanced Edar Signalling Has Pleiotropic Effects on Craniofacial and Cutaneous Glands |journal=PLOS ONE |language=en |volume=4 |issue=10 |pages=e7591 |bibcode=2009PLoSO...4.7591C |doi=10.1371/journal.pone.0007591 |issn=1932-6203 |pmc=2762540 |pmid=19855838 |doi-access=free}} "As this allele attained high frequency in an environment that was notably cold and dry, increased glandular secretions could represent a trait that was positively selected to achieve increased lubrication and reduced evaporation from exposed facial structures and upper airways"

The frequency of 370A is most highly elevated in modern North Asian and East Asian populations, followed by Native American populations, but is virtually absent in other populations around the world. In a study of 222 Korean and 265 Japanese subjects, the 370A mutation was found in 86.9% Korean (Busan) and 77.5% Japanese (Tokyo) subjects.{{Cite journal |last1=Park |first1=Jeong-Heuy |last2=Yamaguchi |first2=Tetsutaro |last3=Watanabe |first3=Chiaki |last4=Kawaguchi |first4=Akira |last5=Haneji |first5=Kuniaki |last6=Takeda |first6=Mayako |last7=Kim |first7=Yong-Il |last8=Tomoyasu |first8=Yoko |last9=Watanabe |first9=Miyuki |last10=Oota |first10=Hiroki |last11=Hanihara |first11=Tsunehiko |last12=Ishida |first12=Hajime |last13=Maki |first13=Koutaro |last14=Park |first14=Soo-Byung |last15=Kimura |first15=Ryosuke |date=August 2012 |title=Effects of an Asian-specific nonsynonymous EDAR variant on multiple dental traits |journal=Journal of Human Genetics |language=en |volume=57 |issue=8 |pages=508–514 |doi=10.1038/jhg.2012.60 |issn=1435-232X |pmid=22648185 |doi-access=free}} Many Native Americans today have significant European admixture and Europeans lack this EDAR variant entirely, so it is likely that the occurrence of 370A among Native Americans was originally much higher prior to the European colonization of the Americas.{{Cite journal |last1=Hlusko |first1=Leslea J. |last2=Carlson |first2=Joshua P. |last3=Chaplin |first3=George |last4=Elias |first4=Scott A. |last5=Hoffecker |first5=John F. |last6=Huffman |first6=Michaela |last7=Jablonski |first7=Nina G. |last8=Monson |first8=Tesla A. |last9=O’Rourke |first9=Dennis H. |last10=Pilloud |first10=Marin A. |last11=Scott |first11=G. Richard |date=2018-05-08 |title=Environmental selection during the last ice age on the mother-to-infant transmission of vitamin D and fatty acids through breast milk |journal=Proceedings of the National Academy of Sciences |language=en |volume=115 |issue=19 |pages=E4426–E4432 |doi=10.1073/pnas.1711788115 |doi-access=free |issn=0027-8424 |pmc=5948952 |pmid=29686092|bibcode=2018PNAS..115E4426H }}

The derived G-allele is a variation of the A-allele in earlier hominids, the version found in most modern non-East Asian and non-Native American populations and is found in 100% of Native American skeletal remains within all Native American haplogroups which studies have been done on prior to all contact from foreign population from Africa, Europe, or Asia. The derived allele was present in both the Tibeto-Burman (Magar and Newar) and Indo-European (Brahmin) populations of Nepal. The highest 1540C allele frequency was observed in Magar (71%), followed by Newar (30%) and Brahmin (20%).{{Cite journal |last1=Basnet |first1=Rajdip |last2=Rai |first2=Niraj |last3=Tamang |first3=Rakesh |last4=Awasthi |first4=Nagendra Prasad |last5=Pradhan |first5=Isha |last6=Parajuli |first6=Pawan |last7=Kashyap |first7=Deepak |last8=Reddy |first8=Alla Govardhan |last9=Chaubey |first9=Gyaneshwer |last10=Das Manandhar |first10=Krishna |last11=Shrestha |first11=Tilak Ram |last12=Thangaraj |first12=Kumarasamy |date=2022-10-15 |title=The matrilineal ancestry of Nepali populations |url=https://link.springer.com/10.1007/s00439-022-02488-z |journal=Human Genetics |volume=142 |issue=2 |pages=167–180 |language=en |doi=10.1007/s00439-022-02488-z |pmid=36242641 |s2cid=252904281 |issn=0340-6717|url-access=subscription }}

50% of ancient DNA samples (7,900-7,500 BP) from Motala, Sweden; two (3300–3000 BC) from the Afanasevo culture and one (400–200 BC) Scythian sample were found to carry the rs3827760 mutation.{{cite journal | vauthors = Mathieson I, Lazaridis I, Rohland N, Mallick S, Patterson N, Roodenberg SA, Harney E, Stewardson K, Fernandes D, Novak M, Sirak K, Gamba C, Jones ER, Llamas B, Dryomov S, Pickrell J, Arsuaga JL, de Castro JM, Carbonell E, Gerritsen F, Khokhlov A, Kuznetsov P, Lozano M, Meller H, Mochalov O, Moiseyev V, Guerra MA, Roodenberg J, Vergès JM, Krause J, Cooper A, Alt KW, Brown D, Anthony D, Lalueza-Fox C, Haak W, Pinhasi R, Reich D | display-authors = 6 | title = Genome-wide patterns of selection in 230 ancient Eurasians | journal = Nature | volume = 528 | issue = 7583 | pages = 499–503 | date = December 2015 | pmid = 26595274 | pmc = 4918750 | doi = 10.1038/nature16152 | bibcode = 2015Natur.528..499M }}

According to a 2018 study, several ancient DNA samples from the Americas, including USR1 from the Upward Sun River site, Anzick-1, and the 9,600 BP individual from Lapa do Santo, were found to not carry the derived allele. This suggests that the increased frequency of the derived allele occurred independently in both East Asia and the Americas.{{cite journal | vauthors = Posth C, Nakatsuka N, Lazaridis I, Skoglund P, Mallick S, Lamnidis TC, Rohland N, Nägele K, Adamski N, Bertolini E, Broomandkhoshbacht N, Cooper A, Culleton BJ, Ferraz T, Ferry M, Furtwängler A, Haak W, Harkins K, Harper TK, Hünemeier T, Lawson AM, Llamas B, Michel M, Nelson E, Oppenheimer J, Patterson N, Schiffels S, Sedig J, Stewardson K, Talamo S, Wang CC, Hublin JJ, Hubbe M, Harvati K, Nuevo Delaunay A, Beier J, Francken M, Kaulicke P, Reyes-Centeno H, Rademaker K, Trask WR, Robinson M, Gutierrez SM, Prufer KM, Salazar-García DC, Chim EN, Müller Plumm Gomes L, Alves ML, Liryo A, Inglez M, Oliveira RE, Bernardo DV, Barioni A, Wesolowski V, Scheifler NA, Rivera MA, Plens CR, Messineo PG, Figuti L, Corach D, Scabuzzo C, Eggers S, DeBlasis P, Reindel M, Méndez C, Politis G, Tomasto-Cagigao E, Kennett DJ, Strauss A, Fehren-Schmitz L, Krause J, Reich D | display-authors = 6 | title = Reconstructing the Deep Population History of Central and South America | journal = Cell | volume = 175 | issue = 5 | pages = 1185–1197.e22 | date = November 2018 | pmid = 30415837 | pmc = 6327247 | doi = 10.1016/j.cell.2018.10.027 | publisher = Elsevier BV | hdl = 10550/67985 }}

A 2021 study analyzed the DNA of 6 Jomon remains from Japan and found that none of them carried the derived EDAR allele that is fixed in modern East Asian populations.{{cite journal |last1=Wang |first1=Chuan-Chao |title=Genomic insights into the formation of human populations in East Asia |journal=Nature |date=March 2021 |volume=591 |issue=7850 |pages=413–419 |doi=10.1038/s41586-021-03336-2 |pmid=33618348 |language=en |issn=1476-4687|pmc=7993749 |bibcode=2021Natur.591..413W }} "None of our reported 6 Jomon individuals carries the derived allele at the EDARV370A variant in the human Ectodysplasin receptor which affects hair, sweat, and mammary glands (Online Table 15), which has been estimated to have arisen in mainland China ~30,000 years ago24 and then swept to high frequency in nearly all Holocene people from mainland East Asia and the Americas."

References

External links

[https://www.ncbi.nlm.nih.gov/books/NBK1112/ GeneReview/NIH/UW entry on Hypohidrotic Ectodermal Dysplasia]

Category:Proteins

Category:Cell-surface receptors

Category:Ectoderm

Category:TNF receptor family