High levels of copy number variation of ampliconic genes across major human Y haplogroups

AbstractDue to its highly repetitive nature, the human male-specific Y chromosome remains understudied. It is important to investigate variation on the Y chromosome to understand its evolution and contribution to phenotypic variation, including infertility. Approximately 20% of the human Y chromosome consists of ampliconic regions which include nine multi-copy gene families. These gene families are expressed exclusively in testes and usually implicated in spermatogenesis. Here, to gain a better understanding of the role of the Y chromosome in human evolution and in determining sexually dimorphic traits, we studied ampliconic gene copy number variation in 100 males representing ten major Y haplogroups world-wide. Copy number was estimated with droplet digital PCR. In contrast to low nucleotide diversity observed on the Y in previous studies, here we show that ampliconic gene copy number diversity is very high. A total of 98 copy-number-based haplotypes were observed among 100 individuals, and haplotypes were sometimes shared by males from very different haplogroups, suggesting homoplasies. The resulting haplotypes did not cluster according to major Y haplogroups. Overall, only three gene families (DATZ, RBMY, TSPY) showed significant differences in copy number among major Y haplogroups, and the haplogroup of an individual could not be predicted based on his ampliconic gene copy numbers. Finally, we found a significant correlation between copy number variation and individual’s height (for three gene families), but not between the former and facial masculinity/femininity. Our results suggest rapid evolution of ampliconic gene copy numbers on the human Y, and we discuss its causes.

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Ribosomal DNA and Stellate gene copy number variation on the Y chromosome of Drosophila melanogaster.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.86.6.1944 ◽

1989 ◽

Vol 86 (6) ◽

pp. 1944-1948 ◽

Cited By ~ 51

Author(s):

E. M. Lyckegaard ◽

A. G. Clark

Keyword(s):

Drosophila Melanogaster ◽

Copy Number Variation ◽

Y Chromosome ◽

Ribosomal Dna ◽

Copy Number ◽

Gene Copy Number ◽

Gene Copy ◽

Gene Copy Number Variation ◽

Number Variation

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Plasmodium copy number variation scan: gene copy numbers evaluation in haploid genomes

Malaria Journal ◽

10.1186/s12936-016-1258-x ◽

2016 ◽

Vol 15 (1) ◽

Cited By ~ 10

Author(s):

Johann Beghain ◽

Anne-Claire Langlois ◽

Eric Legrand ◽

Laura Grange ◽

Nimol Khim ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Gene Copy ◽

Copy Numbers ◽

Number Variation ◽

Gene Copy Numbers

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Evolutionary and functional analysis of RBMY1 gene copy number variation on the human Y chromosome

Human Molecular Genetics ◽

10.1093/hmg/ddz101 ◽

2019 ◽

Vol 28 (16) ◽

pp. 2785-2798 ◽

Cited By ~ 2

Author(s):

Wentao Shi ◽

Sandra Louzada ◽

Marina Grigorova ◽

Andrea Massaia ◽

Elena Arciero ◽

...

Keyword(s):

Copy Number Variation ◽

Y Chromosome ◽

Sperm Motility ◽

Copy Number ◽

Population Variation ◽

Gene Copy ◽

Copy Numbers ◽

Fish Samples ◽

Number Variation ◽

Fibre Fish

Abstract Human RBMY1 genes are located in four variable-sized clusters on the Y chromosome, expressed in male germ cells and possibly associated with sperm motility. We have re-investigated the mutational background and evolutionary history of the RBMY1 copy number distribution in worldwide samples and its relevance to sperm parameters in an Estonian cohort of idiopathic male factor infertility subjects. We estimated approximate RBMY1 copy numbers in 1218 1000 Genomes Project phase 3 males from sequencing read-depth, then chose 14 for valid ation by multicolour fibre-FISH. These fibre-FISH samples provided accurate calibration standards for the entire panel and led to detailed insights into population variation and mutational mechanisms. RBMY1 copy number worldwide ranged from 3 to 13 with a mode of 8. The two larger proximal clusters were the most variable, and additional duplications, deletions and inversions were detected. Placing the copy number estimates onto the published Y-SNP-based phylogeny of the same samples suggested a minimum of 562 mutational changes, translating to a mutation rate of 2.20 × 10−3 (95% CI 1.94 × 10−3 to 2.48 × 10−3) per father-to-son Y-transmission, higher than many short tandem repeat (Y-STRs), and showed no evidence for selection for increased or decreased copy number, but possible copy number stabilizing selection. An analysis of RBMY1 copy numbers among 376 infertility subjects failed to replicate a previously reported association with sperm motility and showed no significant effect on sperm count and concentration, serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone levels or testicular and semen volume. These results provide the first in-depth insights into the structural rearrangements underlying RBMY1 copy number variation across diverse human lineages.

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Faculty Opinions recommendation of Diet and the evolution of human amylase gene copy number variation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1092307.546722 ◽

2007 ◽

Author(s):

Magnus Ingelman-Sundberg

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Gene Copy Number ◽

Gene Copy ◽

Amylase Gene ◽

Gene Copy Number Variation ◽

Number Variation

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What a finding of gene copy number variation can add to the diagnosis of developmental neuropsychiatric disorders

Current Opinion in Genetics & Development ◽

10.1016/j.gde.2020.12.017 ◽

2021 ◽

Vol 68 ◽

pp. 18-25

Author(s):

Jacob Vorstman ◽

Stephen W Scherer

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Gene Copy Number ◽

Neuropsychiatric Disorders ◽

Gene Copy ◽

Gene Copy Number Variation ◽

Number Variation

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Induction of direct repeat recombination by psoralen–DNA adducts in Saccharomyces cerevisiae: Defects in DNA repair increase gene copy number variation

DNA Repair ◽

10.1016/j.dnarep.2014.05.011 ◽

2014 ◽

Vol 21 ◽

pp. 87-96 ◽

Cited By ~ 2

Author(s):

Wilma A. Saffran ◽

Anam Ahmed ◽

Olga Binyaminov ◽

Cynthia Gonzalez ◽

Amita Gupta ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Dna Repair ◽

Copy Number Variation ◽

Dna Adducts ◽

Copy Number ◽

Gene Copy Number ◽

Direct Repeat ◽

Gene Copy ◽

Gene Copy Number Variation ◽

Number Variation

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Genetic variability of CYP2D6, CYP3A4 and CYP3A5 among the Egyptian population

Pharmacogenomics ◽

10.2217/pgs-2020-0140 ◽

2021 ◽

Author(s):

Thuraya M Mutawi ◽

Mohamed M Zedan ◽

Raida S Yahya ◽

Mahmoud M Zakria ◽

Mamdouh R El-Sawi ◽

...

Keyword(s):

Genetic Variability ◽

Copy Number Variation ◽

Copy Number ◽

Middle Eastern ◽

Gene Copy Number ◽

Gene Copy ◽

Allelic Variants ◽

Gene Copy Number Variation ◽

Number Variation ◽

Study Participants

Aim: This study investigated major allelic variants of CYP2D6, CYP3A4 and CYP3A5 in Egyptians, an Arabic population for which there is little information regarding these important pharmacogenes. Patients & methods: CYP2D6*2, *4, *5, *10, *41 and gene copy number variation, as well as CYP3A4*22 and CYP3A5*3 were determined with commercially available TaqMan assays in 145 healthy study participants. Results: The CYP2D6 alleles identified suggest that the prevalence of poor metabolizers is low as none were found among the 145 subjects investigated. The frequency for CYP3A5 nonexpressers was 74.5% and the CYP3A4*22 allele frequency was low at 2.0%. Conclusion: These preliminary findings indicate that pharmacogene variation in Egyptians is different from those of other Middle Eastern/Arabic populations and warrants further investigation.

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