Mammalian Y Chromosomes Retain Widely Expressed Dosage-sensitive Regulators

Overview

Journal Nature

Specialty Science

Date 2014 Apr 25

PMID 24759411

Citations 346

Authors

Daniel W Bellott

Jennifer F Hughes

Helen Skaletsky

Laura G Brown

Tatyana Pyntikova

Ting-Jan Cho

Natalia Koutseva

Sara Zaghlul

Tina Graves

Susie Rock

Colin Kremitzki

Robert S Fulton

Shannon Dugan

Yan Ding

Donna Morton

Ziad Khan

Lora Lewis

Christian Buhay

Qiaoyan Wang

Jennifer Watt

Michael Holder

Sandy Lee

Lynne Nazareth

Jessica Alfoldi

Steve Rozen

Donna M Muzny

Wesley C Warren

Richard A Gibbs

Richard K Wilson

David C Page

Affiliations

Soon will be listed here.

Abstract

The human X and Y chromosomes evolved from an ordinary pair of autosomes, but millions of years ago genetic decay ravaged the Y chromosome, and only three per cent of its ancestral genes survived. We reconstructed the evolution of the Y chromosome across eight mammals to identify biases in gene content and the selective pressures that preserved the surviving ancestral genes. Our findings indicate that survival was nonrandom, and in two cases, convergent across placental and marsupial mammals. We conclude that the gene content of the Y chromosome became specialized through selection to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly expressed regulators of transcription, translation and protein stability. We propose that beyond its roles in testis determination and spermatogenesis, the Y chromosome is essential for male viability, and has unappreciated roles in Turner's syndrome and in phenotypic differences between the sexes in health and disease.

Citing Articles

Diverse mechanisms of DDX3Y suppression by DDX3X.

Xu X, Wei S bioRxiv. 2025; .

PMID: 39975375 PMC: 11839027. DOI: 10.1101/2025.02.08.637260.

Elevated levels of neutrophils with a pro-inflammatory profile in Turner syndrome across karyotypes.

Just J, Ridder L, Johannsen E, Jensen J, Petersen M, Christensen H NPJ Genom Med. 2025; 10(1):9.

PMID: 39915521 PMC: 11803089. DOI: 10.1038/s41525-025-00467-7.

Evolutionary divergence between homologous X-Y chromosome genes shapes sex-biased biology.

DeCasien A, Tsai K, Liu S, Thomas A, Raznahan A Nat Ecol Evol. 2025; 9(3):448-463.

PMID: 39856216 DOI: 10.1038/s41559-024-02627-x.

Systematic identification of Y-chromosome gene functions in mouse spermatogenesis.

Subrini J, Varsally W, Balsells I, Bensberg M, Sioutas G, Ojarikre O Science. 2025; 387(6732):393-400.

PMID: 39847625 PMC: 7617377. DOI: 10.1126/science.ads6495.

Post-transcriptional cross- and auto-regulation buffer expression of the human RNA helicases and .

Rengarajan S, Derks J, Bellott D, Slavov N, Page D Genome Res. 2025; 35(1):20-30.

PMID: 39794123 PMC: 11789639. DOI: 10.1101/gr.279707.124.

References

Skaletsky H, Brown L, Minx P, Cordum H, Waterston R, Wilson R . The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat Genet. 2001; 29(3):279-86. DOI: 10.1038/ng757. View

Jegalian K, Page D . A proposed path by which genes common to mammalian X and Y chromosomes evolve to become X inactivated. Nature. 1998; 394(6695):776-80. DOI: 10.1038/29522. View

Hook E, Warburton D . The distribution of chromosomal genotypes associated with Turner's syndrome: livebirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosaicism. Hum Genet. 1983; 64(1):24-7. DOI: 10.1007/BF00289473. View

Zinn A, Tonk V, Chen Z, Flejter W, Gardner H, Guerra R . Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1. Am J Hum Genet. 1998; 63(6):1757-66. PMC: 1377648. DOI: 10.1086/302152. View

Ross M, Grafham D, Coffey A, Scherer S, McLay K, Muzny D . The DNA sequence of the human X chromosome. Nature. 2005; 434(7031):325-37. PMC: 2665286. DOI: 10.1038/nature03440. View

Mueller J, Skaletsky H, Brown L, Zaghlul S, Rock S, Graves T . Independent specialization of the human and mouse X chromosomes for the male germ line. Nat Genet. 2013; 45(9):1083-7. PMC: 3758364. DOI: 10.1038/ng.2705. View

Rujirabanjerd S, Nelson J, Tarpey P, Hackett A, Edkins S, Raymond F . Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype-phenotype correlation. Eur J Hum Genet. 2009; 18(3):330-5. PMC: 2987212. DOI: 10.1038/ejhg.2009.175. View

Zinn A, Ouyang B, Ross J, Varma S, Bourgeois M, Tonk V . Del (X)(p21.2) in a mother and two daughters with variable ovarian function. Clin Genet. 1998; 52(4):235-9. DOI: 10.1111/j.1399-0004.1997.tb02554.x. View

Burgoyne P, Tam P, Evans E . Retarded development of XO conceptuses during early pregnancy in the mouse. J Reprod Fertil. 1983; 68(2):387-93. DOI: 10.1530/jrf.0.0680387. View

10.

Lee S, Lee J, Lee S . UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program. Dev Cell. 2011; 22(1):25-37. PMC: 4111644. DOI: 10.1016/j.devcel.2011.11.009. View

11.

Watanabe M, Zinn A, Page D, Nishimoto T . Functional equivalence of human X- and Y-encoded isoforms of ribosomal protein S4 consistent with a role in Turner syndrome. Nat Genet. 1993; 4(3):268-71. DOI: 10.1038/ng0793-268. View

12.

Huang N, Lee I, Marcotte E, Hurles M . Characterising and predicting haploinsufficiency in the human genome. PLoS Genet. 2010; 6(10):e1001154. PMC: 2954820. DOI: 10.1371/journal.pgen.1001154. View

13.

Hughes J, Skaletsky H, Brown L, Pyntikova T, Graves T, Fulton R . Strict evolutionary conservation followed rapid gene loss on human and rhesus Y chromosomes. Nature. 2012; 483(7387):82-6. PMC: 3292678. DOI: 10.1038/nature10843. View

14.

Sinclair A, Berta P, Palmer M, Hawkins J, GRIFFITHS B, Smith M . A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990; 346(6281):240-4. DOI: 10.1038/346240a0. View

15.

Wang X, Douglas K, VandeBerg J, Clark A, Samollow P . Chromosome-wide profiling of X-chromosome inactivation and epigenetic states in fetal brain and placenta of the opossum, Monodelphis domestica. Genome Res. 2013; 24(1):70-83. PMC: 3875863. DOI: 10.1101/gr.161919.113. View

16.

Rozen S, Marszalek J, Alagappan R, Skaletsky H, Page D . Remarkably little variation in proteins encoded by the Y chromosome's single-copy genes, implying effective purifying selection. Am J Hum Genet. 2009; 85(6):923-8. PMC: 2790577. DOI: 10.1016/j.ajhg.2009.11.011. View

17.

Sekiguchi T, Iida H, Fukumura J, Nishimoto T . Human DDX3Y, the Y-encoded isoform of RNA helicase DDX3, rescues a hamster temperature-sensitive ET24 mutant cell line with a DDX3X mutation. Exp Cell Res. 2004; 300(1):213-22. DOI: 10.1016/j.yexcr.2004.07.005. View

18.

Lindgren A, Hoyos T, Talkowski M, Hanscom C, Blumenthal I, Chiang C . Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate. Hum Genet. 2013; 132(5):537-52. PMC: 3627823. DOI: 10.1007/s00439-013-1263-x. View

19.

Froyen G, Belet S, Martinez F, Santos-Reboucas C, Declercq M, Verbeeck J . Copy-number gains of HUWE1 due to replication- and recombination-based rearrangements. Am J Hum Genet. 2012; 91(2):252-64. PMC: 3415555. DOI: 10.1016/j.ajhg.2012.06.010. View

20.

Burgoyne P, Evans E, Holland K . XO monosomy is associated with reduced birthweight and lowered weight gain in the mouse. J Reprod Fertil. 1983; 68(2):381-5. DOI: 10.1530/jrf.0.0680381. View