1. Genetics and Genomics

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

  1. Sara A Carioscia
  2. Kathryn J Weaver
  3. Andrew N Bortvin
  4. Hao Pan
  5. Daniel Ariad
  6. Avery Davis Bell
  7. Rajiv C McCoy  Is a corresponding author
  1. Johns Hopkins University, United States
  2. Georgia Institute of Technology, United States
https://doi.org/10.7554/eLife.76383
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  1. Sara A Carioscia
  2. Kathryn J Weaver
  3. Andrew N Bortvin
  4. Hao Pan
  5. Daniel Ariad
  6. Avery Davis Bell
  7. Rajiv C McCoy
(2022)
A method for low-coverage single-gamete sequence analysis demonstrates adherence to Mendel's first law across a large sample of human sperm
eLife 11:e76383.
https://doi.org/10.7554/eLife.76383
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Abstract

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.

Data availability

Data analysis scripts specific to our study are available at https://github.com/mccoy-lab/transmission-distortion. Our package rhapsodi is available at: https://github.com/mccoy-lab/rhapsodi.Raw sperm sequencing data from Bell et al. (2020) can be accessed via dbGaP (study accession number phs001887.v1.p1), as described in the original publication. Raw sperm sequencing data from Leung et al. (2021) was accessed upon request from the authors. We filtered the cells in our analysis using metadata published by Bell et al. (2020) at: https://zenodo.org/record/3561081#.YLAdO2ZKhb9. Analogous metadata from Leung et al. (2021) was obtained upon request from the authors.

The following previously published data sets were used

Article and author information

Author details

  1. Sara A Carioscia

    Department of Biology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.

  2. Kathryn J Weaver

    Department of Biology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.

  3. Andrew N Bortvin

    Department of Biology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.

  4. Hao Pan

    Department of Biology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.

  5. Daniel Ariad

    Department of Biology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.

  6. Avery Davis Bell

    School of Biological Sciences, Georgia Institute of Technology, Atlanta, United States
    Competing interests
    Avery Davis Bell, is an inventor on a US Patent Application (US20210230667A1, applicant: President and Fellows of Harvard College) relating to the Sperm-seq single-cell sequencing method. Was an occasional consultant for Ohana Biosciences between October 2019 and March 2020..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1837-302X

  7. Rajiv C McCoy

    Department of Biology, Johns Hopkins University, Baltimore, United States
    For correspondence
    rajiv.mccoy@jhu.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0615-146X

Funding

National Science Foundation (1746891)

  • Sara A Carioscia

National Institutes of Health (R35GM133747)

  • Rajiv C McCoy

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2022, Carioscia et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sara A Carioscia
  2. Kathryn J Weaver
  3. Andrew N Bortvin
  4. Hao Pan
  5. Daniel Ariad
  6. Avery Davis Bell
  7. Rajiv C McCoy
(2022)
A method for low-coverage single-gamete sequence analysis demonstrates adherence to Mendel's first law across a large sample of human sperm
eLife 11:e76383.
https://doi.org/10.7554/eLife.76383

Share this article

https://doi.org/10.7554/eLife.76383

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