Evidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans

Ping Hsun Hsieh; Vy Dang; Mitchell R. Vollger; Yafei Mao; Tzu Hsueh Huang; Philip C. Dishuck; Carl Baker; Stuart Cantsilieris; Alexandra P. Lewis; Katherine M. Munson; Melanie Sorensen; Anne Marie E. Welch; Jason G. Underwood; Evan E. Eichler

doi:10.1038/s41467-021-25435-4

Evidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans

Ping Hsun Hsieh, Vy Dang, Mitchell R. Vollger, Yafei Mao, Tzu Hsueh Huang, Philip C. Dishuck, Carl Baker, Stuart Cantsilieris, Alexandra P. Lewis, Katherine M. Munson, Melanie Sorensen, Anne Marie E. Welch, Jason G. Underwood, Evan E. Eichler

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

TRP channel-associated factor 1/2 (TCAF1/TCAF2) proteins antagonistically regulate the cold-sensor protein TRPM8 in multiple human tissues. Understanding their significance has been complicated given the locus spans a gap-ridden region with complex segmental duplications in GRCh38. Using long-read sequencing, we sequence-resolve the locus, annotate full-length TCAF models in primate genomes, and show substantial human-specific TCAF copy number variation. We identify two human super haplogroups, H4 and H5, and establish that TCAF duplications originated ~1.7 million years ago but diversified only in Homo sapiens by recurrent structural mutations. Conversely, in all archaic-hominin samples the fixation for a specific H4 haplotype without duplication is likely due to positive selection. Here, our results of TCAF copy number expansion, selection signals in hominins, and differential TCAF2 expression between haplogroups and high TCAF2 and TRPM8 expression in liver and prostate in modern-day humans imply TCAF diversification among hominins potentially in response to cold or dietary adaptations.

Original language	English (US)
Article number	5118
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25435-4
State	Published - Dec 1 2021
Externally published	Yes

Bibliographical note

Funding Information:
The authors thank T. Brown for assistance in editing this manuscript. We also thank S.C. Murali and D.S. Gordon for help submitting data to the NCBI database. Funding: This work was supported, in part, by the US National Institutes of Health (NIH) grant R01HG002385 to E.E.E. P.H. is supported by the NIH Pathway to Independence Award (NHGRI, K99HG011041). S.C. was supported by a National Health and Medical Research Council (NHMRC) C. J. Martin Biomedical Fellowship (1073726). E.E.E. is an investigator of the Howard Hughes Medical Institute.

Publisher Copyright:
© 2021, The Author(s).

Publisher link

10.1038/s41467-021-25435-4

Find It

Find It at U of M Libraries

Cite this

Hsieh, P. H., Dang, V., Vollger, M. R., Mao, Y., Huang, T. H., Dishuck, P. C., Baker, C., Cantsilieris, S., Lewis, A. P., Munson, K. M., Sorensen, M., Welch, A. M. E., Underwood, J. G., & Eichler, E. E. (2021). Evidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans. Nature communications, 12(1), Article 5118. https://doi.org/10.1038/s41467-021-25435-4

Hsieh, PH, Dang, V, Vollger, MR, Mao, Y, Huang, TH, Dishuck, PC, Baker, C, Cantsilieris, S, Lewis, AP, Munson, KM, Sorensen, M, Welch, AME, Underwood, JG & Eichler, EE 2021, 'Evidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans', Nature communications, vol. 12, no. 1, 5118. https://doi.org/10.1038/s41467-021-25435-4

@article{9e5ebd1ee99e44d780d181f19626800b,

title = "Evidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans",

abstract = "TRP channel-associated factor 1/2 (TCAF1/TCAF2) proteins antagonistically regulate the cold-sensor protein TRPM8 in multiple human tissues. Understanding their significance has been complicated given the locus spans a gap-ridden region with complex segmental duplications in GRCh38. Using long-read sequencing, we sequence-resolve the locus, annotate full-length TCAF models in primate genomes, and show substantial human-specific TCAF copy number variation. We identify two human super haplogroups, H4 and H5, and establish that TCAF duplications originated ~1.7 million years ago but diversified only in Homo sapiens by recurrent structural mutations. Conversely, in all archaic-hominin samples the fixation for a specific H4 haplotype without duplication is likely due to positive selection. Here, our results of TCAF copy number expansion, selection signals in hominins, and differential TCAF2 expression between haplogroups and high TCAF2 and TRPM8 expression in liver and prostate in modern-day humans imply TCAF diversification among hominins potentially in response to cold or dietary adaptations.",

author = "Hsieh, {Ping Hsun} and Vy Dang and Vollger, {Mitchell R.} and Yafei Mao and Huang, {Tzu Hsueh} and Dishuck, {Philip C.} and Carl Baker and Stuart Cantsilieris and Lewis, {Alexandra P.} and Munson, {Katherine M.} and Melanie Sorensen and Welch, {Anne Marie E.} and Underwood, {Jason G.} and Eichler, {Evan E.}",

note = "Funding Information: The authors thank T. Brown for assistance in editing this manuscript. We also thank S.C. Murali and D.S. Gordon for help submitting data to the NCBI database. Funding: This work was supported, in part, by the US National Institutes of Health (NIH) grant R01HG002385 to E.E.E. P.H. is supported by the NIH Pathway to Independence Award (NHGRI, K99HG011041). S.C. was supported by a National Health and Medical Research Council (NHMRC) C. J. Martin Biomedical Fellowship (1073726). E.E.E. is an investigator of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-25435-4",

language = "English (US)",

volume = "12",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Evidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans

AU - Hsieh, Ping Hsun

AU - Dang, Vy

AU - Vollger, Mitchell R.

AU - Mao, Yafei

AU - Huang, Tzu Hsueh

AU - Dishuck, Philip C.

AU - Baker, Carl

AU - Cantsilieris, Stuart

AU - Lewis, Alexandra P.

AU - Munson, Katherine M.

AU - Sorensen, Melanie

AU - Welch, Anne Marie E.

AU - Underwood, Jason G.

AU - Eichler, Evan E.

N1 - Funding Information: The authors thank T. Brown for assistance in editing this manuscript. We also thank S.C. Murali and D.S. Gordon for help submitting data to the NCBI database. Funding: This work was supported, in part, by the US National Institutes of Health (NIH) grant R01HG002385 to E.E.E. P.H. is supported by the NIH Pathway to Independence Award (NHGRI, K99HG011041). S.C. was supported by a National Health and Medical Research Council (NHMRC) C. J. Martin Biomedical Fellowship (1073726). E.E.E. is an investigator of the Howard Hughes Medical Institute. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - TRP channel-associated factor 1/2 (TCAF1/TCAF2) proteins antagonistically regulate the cold-sensor protein TRPM8 in multiple human tissues. Understanding their significance has been complicated given the locus spans a gap-ridden region with complex segmental duplications in GRCh38. Using long-read sequencing, we sequence-resolve the locus, annotate full-length TCAF models in primate genomes, and show substantial human-specific TCAF copy number variation. We identify two human super haplogroups, H4 and H5, and establish that TCAF duplications originated ~1.7 million years ago but diversified only in Homo sapiens by recurrent structural mutations. Conversely, in all archaic-hominin samples the fixation for a specific H4 haplotype without duplication is likely due to positive selection. Here, our results of TCAF copy number expansion, selection signals in hominins, and differential TCAF2 expression between haplogroups and high TCAF2 and TRPM8 expression in liver and prostate in modern-day humans imply TCAF diversification among hominins potentially in response to cold or dietary adaptations.

AB - TRP channel-associated factor 1/2 (TCAF1/TCAF2) proteins antagonistically regulate the cold-sensor protein TRPM8 in multiple human tissues. Understanding their significance has been complicated given the locus spans a gap-ridden region with complex segmental duplications in GRCh38. Using long-read sequencing, we sequence-resolve the locus, annotate full-length TCAF models in primate genomes, and show substantial human-specific TCAF copy number variation. We identify two human super haplogroups, H4 and H5, and establish that TCAF duplications originated ~1.7 million years ago but diversified only in Homo sapiens by recurrent structural mutations. Conversely, in all archaic-hominin samples the fixation for a specific H4 haplotype without duplication is likely due to positive selection. Here, our results of TCAF copy number expansion, selection signals in hominins, and differential TCAF2 expression between haplogroups and high TCAF2 and TRPM8 expression in liver and prostate in modern-day humans imply TCAF diversification among hominins potentially in response to cold or dietary adaptations.

UR - http://www.scopus.com/inward/record.url?scp=85113495171&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85113495171&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-25435-4

DO - 10.1038/s41467-021-25435-4

M3 - Article

C2 - 34433829

AN - SCOPUS:85113495171

SN - 2041-1723

VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 5118

ER -

Evidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans

Abstract

Bibliographical note

Publisher link

Find It

Other files and links

Fingerprint

Cite this