Single cell analysis of DNA in more than 10,000 individual sperm from men with abnormal reproductive outcomes

Leung, Angela Q.; Bell, Avery Davis; Mello, Curtis J.; Penzias, Alan S.; McCarroll, Steven A.; Sakkas, Denny

doi:10.1007/s10815-021-02300-3

Cited by 2 publications

(11 citation statements)

References 36 publications

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“…rhapsodi is designed to work for large existing datasets such as Sperm-seq ( Bell et al, 2020 ; Leung et al, 2021 ) and to remain applicable as future single-gamete sequencing datasets grow in size. Specifically, rhapsodi was rigorously benchmarked for datasets containing up to 5000 gametes per donor with 100,000 SNPs per chromosome at coverages up to 2.3× ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…Given the strong performance of our method on simulated data, we proceeded to analyze published ( Bell et al, 2020 ; Leung et al, 2021 ) single-cell DNA sequencing data from 41,189 human sperm (969–3377 cells from each of 25 donors) ( Figure 5—figure supplement 1 ). These data possessed an average sequencing depth of ∼0.01× coverage per cell, with a range of ∼0.002× to ∼0.03×.…”

Section: Resultsmentioning

confidence: 99%

“…These data possessed an average sequencing depth of ∼0.01× coverage per cell, with a range of ∼0.002× to ∼0.03×. Of the 25 sperm donors, samples from 20 individuals were obtained from a sperm bank and were of presumed (but unknown) normal fertility status ( Bell et al, 2020 ), while five donors had known reproductive issues (failed fertilization after intracytoplasmic sperm injection [ n =2] or poor blastocyst formation [ n =3]) ( Leung et al, 2021 ). Using principal component analysis, we compared the genetic similarity of each donor individual to globally diverse populations from the 1000 Genomes Project ( Auton et al, 2015 , Figure 5—figure supplement 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…The recent development of high-throughput single-cell genome sequencing of human sperm (termed “Sperm-seq”) ( Bell et al, 2020 ; Leung et al, 2021 ) offers an opportunity to study various aspects of meiosis and inheritance with improved statistical power. Using a highly multiplexed droplet-based approach, Sperm-seq facilitated sequencing of thousands of sperm from each of 25 donor individuals (

=41,189 total cells), in turn revealing detailed patterns of meiotic recombination and aneuploidy.…”

Section: Introductionmentioning

confidence: 99%

“…To address these limitations, we applied rhapsodi to published single-cell sequencing data from 41,189 human sperm (969–3377 cells from each of 25 donors) ( Bell et al, 2020 ; Leung et al, 2021 ). After stringent filtering for segmental duplications and other sources of genotyping error, our results exhibited close concordance with null expectations under Mendelian inheritance, both with regard to individual loci and to aggregate genome-wide signal.…”

Section: Introductionmentioning

confidence: 99%

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A method for low-coverage single-gamete sequence analysis demonstrates adherence to Mendel’s first law across a large sample of human sperm

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eLife

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Recently published single-cell sequencing data from individual human sperm (n = 41,189; 969-3,377 cells from each of 25 donors) offer an opportunity to investigate questions of inheritance with improved statistical power, but require new methods tailored to these extremely low-coverage data (∼0.01 x per cell). To this end, we developed a method, named rhapsodi, that leverages sparse gamete genotype data to phase the diploid genomes of the donor individuals, impute missing gamete genotypes, and discover meiotic recombination breakpoints, benchmarking its performance across a wide range of study designs. Mendel's Law of Segregation states that the offspring of a diploid, heterozygous parent will inherit either allele with equal probability. While the vast majority of loci adhere to this rule, research in model and non-model organisms has uncovered numerous exceptions whereby 'selfish' alleles are disproportionately transmitted to the next generation. Evidence of such 'transmission distortion' (TD) in humans remains equivocal in part because scans of human pedigrees have been under-powered to detect small effects. After applying rhapsodi to the sperm sequencing data, we therefore scanned the gametes for evidence of TD. Our results exhibited close concordance with binomial expectations under balanced transmission. Together, our work demonstrates that rhapsodi can facilitate novel uses of inferred genotype data and meiotic recombination events, while offering a powerful quantitative framework for testing for TD in other cohorts and study systems.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

=41,189 total cells), in turn revealing detailed patterns of meiotic recombination and aneuploidy.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A method for low-coverage single-gamete sequence analysis demonstrates adherence to Mendel’s first law across a large sample of human sperm

Carioscia

Weaver

Bortvin

et al. 2022

eLife

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View full text Add to dashboard Cite

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Strict adherence to Mendel’s First Law across a large sample of human sperm genomes

Carioscia

Weaver

Bortvin

et al. 2021

Preprint

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Mendel’s Law of Segregation states that the offspring of a diploid, heterozygous parent will inherit either allele with equal probability. While the vast majority of loci adhere to this rule, research in model and non-model organisms has uncovered numerous exceptions whereby “selfish” alleles are disproportionately transmitted to the next generation. Evidence of such “transmission distortion” (TD) in humans remains equivocal in part because scans of human pedigrees have been under-powered to detect small effects. Recently published single-cell sequencing data from individual human sperm (n = 41,189; 969-3,377 cells from each of 25 donors) offer an opportunity to revisit this question with unprecedented statistical power, but require new methods tailored to extremely low-coverage data (~0.01× per cell). To this end, we developed a method, named rhapsodi, that leverages sparse gamete genotype data to phase the diploid genomes of the donor individuals, impute missing gamete genotypes, and discover meiotic recombination breakpoints, benchmarking its performance across a wide range of study designs. After applying rhapsodi to the sperm sequencing data, we then scanned the gametes for evidence of TD. Our results exhibited close concordance with binomial expectations under balanced transmission, in contrast to tenuous signals of TD that were previously reported in pedigree-based studies. Together, our work excludes the existence of even weak TD in this sample, while offering a powerful quantitative framework for testing this and related hypotheses in other cohorts and study systems.

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Single cell analysis of DNA in more than 10,000 individual sperm from men with abnormal reproductive outcomes

Cited by 2 publications

References 36 publications

A method for low-coverage single-gamete sequence analysis demonstrates adherence to Mendel’s first law across a large sample of human sperm

A method for low-coverage single-gamete sequence analysis demonstrates adherence to Mendel’s first law across a large sample of human sperm

Strict adherence to Mendel’s First Law across a large sample of human sperm genomes

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