Selection Has Countered High Mutability to Preserve the Ancestral Copy Number of Y Chromosome Amplicons in Diverse Human Lineages

Teitz, Levi S.; Pyntikova, Tatyana; Skaletsky, Helen; Page, David C.

doi:10.1016/j.ajhg.2018.07.007

Cited by 38 publications

(91 citation statements)

References 74 publications

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“…Collectively, our results suggest that Sdic CNV in contemporary populations of D. melanogaster secures a minimal necessary expression level across different genomic backgrounds and sexual selection regimes, serving also as a substrate to prevent nucleotide change via gene conversion and NAHR events for essentially all the Sdic repeat but the two most 3′ exons and the 3′-UTR of Sdic copies ( Rozen et al. 2003 ; Teitz et al. 2018 ).…”

Section: Discussionmentioning

confidence: 80%

“…In contrast, we found that intermediate CN values are prevalent, that differences in the aggregate transcript abundance are not correlated with CNV in a geographically diverse set of strains, and that significantly increased Sdic expression as a result of artificially doubling CN does not result in enhanced sperm competitive ability based on progeny contribution in double-mating assays. The prevalence of individuals bearing intermediate CN values could result from a scenario of stabilizing selection, or from a mutation-drift equilibrium coupled with the action of purifying selection sculpting the range boundaries as proposed for some multigene families in mammals ( Hollox 2008 ; Teitz et al. 2018 ).…”

Section: Discussionmentioning

confidence: 99%

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Understanding the Early Evolutionary Stages of a Tandem Drosophilamelanogaster-Specific Gene Family: A Structural and Functional Population Study

Clifton

Jimenez

et al. 2020

Molecular Biology and Evolution

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Gene families underlie genetic innovation and phenotypic diversification. However, our understanding of the early genomic and functional evolution of tandemly arranged gene families remains incomplete as paralog sequence similarity hinders their accurate characterization. The Drosophila melanogaster-specific gene family Sdic is tandemly repeated and impacts sperm competition. We scrutinized Sdic in 20 geographically diverse populations using reference-quality genome assemblies, read-depth methodologies, and qPCR, finding that ∼90% of the individuals harbor 3–7 copies as well as evidence of population differentiation. In strains with reliable gene annotations, copy number variation (CNV) and differential transposable element insertions distinguish one structurally distinct version of the Sdic region per strain. All 31 annotated copies featured protein-coding potential and, based on the protein variant encoded, were categorized into 13 paratypes differing in their 3′ ends, with 3–5 paratypes coexisting in any strain examined. Despite widespread gene conversion, the only copy present in all strains has functionally diverged at both coding and regulatory levels under positive selection. Contrary to artificial tandem duplications of the Sdic region that resulted in increased male expression, CNV in cosmopolitan strains did not correlate with expression levels, likely as a result of differential genome modifier composition. Duplicating the region did not enhance sperm competitiveness, suggesting a fitness cost at high expression levels or a plateau effect. Beyond facilitating a minimally optimal expression level, Sdic CNV acts as a catalyst of protein and regulatory diversity, showcasing a possible evolutionary path recently formed tandem multigene families can follow toward long-term consolidation in eukaryotic genomes.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Understanding the Early Evolutionary Stages of a Tandem Drosophilamelanogaster-Specific Gene Family: A Structural and Functional Population Study

Clifton

Jimenez

et al. 2020

Molecular Biology and Evolution

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“…The high level of variation in RBMY1 copy number (second on the Y chromosome only to TSPY (24)) has been well established by previous studies in several populations such as the UK (12), Denmark (13), China (17) and worldwide samples (14,15) including those from the 1000 Genomes Project (16,19). The data were generated using diverse techniques: array CGH (12,19), sequencing (14–16,19) or ddPCR (17), and thus this conclusion, confirmed by the present work, is well established.…”

Section: Discussionmentioning

confidence: 84%

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

Shi

Louzada

Grigorova

et al. 2019

Human Molecular Genetics

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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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“…Given that partial AZFc deletions perturb AZFc gene dosage, we were interested in analyzing the role of an increased gene dosage (>4 for DAZ and >2 for CDY1, respectively) due to partial duplications. Although case/ control association studies failed to reach to a univocal conclusion in respect to the hypothetical "optimal" AZFc gene dosage needed for normal spermatogenesis [27,30,34,35], it seems that a positive selection for an "optimal" gene dosage does exist (four DAZ and two CDY1 copies) during evolution [36]. Hence, our working hypothesis was a possible predisposing effect of AZFc dosage variation (not only deficit but also an excess) to TGCT development.…”

Section: Discussionmentioning

confidence: 82%

gr/gr deletion predisposes to testicular germ cell tumour independently from altered spermatogenesis: results from the largest European study

et al. 2019

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The association between impaired spermatogenesis and TGCT has stimulated research on shared genetic factors. Y chromosome-linked partial AZFc deletions predispose to oligozoospermia and were also studied in TGCT patients with controversial results. In the largest study reporting the association between gr/gr deletion and TGCT, sperm parameters were unknown. Hence, it remains to be established whether this genetic defect truly represents a common genetic link between TGCT and impaired sperm production. Our aim was to explore the role of the following Y chromosome-linked factors in the predisposition to TGCT: (i) gr/gr deletion in subjects with known sperm parameters; (ii) other partial AZFc deletions and, for the first time, the role of partial AZFc duplications; (iii) DAZ gene dosage variation. 497 TGCT patients and 2030 controls from two Mediterranean populations with full semen/andrological characterization were analyzed through a series of molecular genetic techniques. Our most interesting finding concerns the gr/gr deletion and DAZ gene dosage variation (i.e., DAZ copy number is different from the reference sequence), both conferring TGCT susceptibility. In particular, the highest risk was observed when normozoospermic TGCT and normozoospermic controls were compared (OR = 3.7; 95% CI = 1.5-9.1; p = 0.006 for gr/gr deletion and OR = 1.8; 95% CI = 1.1-3.0; p = 0.013 for DAZ gene dosage alteration). We report in the largest European study population the predisposing effect of gr/gr deletion to TGCT as an independent risk factor from impaired spermatogenesis. Our finding implies regular tumour screening/follow-up in male family members of TGCT patients with gr/gr deletion and in infertile gr/gr deletion carriers.

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Selection Has Countered High Mutability to Preserve the Ancestral Copy Number of Y Chromosome Amplicons in Diverse Human Lineages

Cited by 38 publications

References 74 publications

Understanding the Early Evolutionary Stages of a Tandem Drosophilamelanogaster-Specific Gene Family: A Structural and Functional Population Study

Understanding the Early Evolutionary Stages of a Tandem Drosophilamelanogaster-Specific Gene Family: A Structural and Functional Population Study

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

gr/gr deletion predisposes to testicular germ cell tumour independently from altered spermatogenesis: results from the largest European study

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