PT  - JOURNAL ARTICLE
AU  - Sara A. Carioscia
AU  - Kathryn J. Weaver
AU  - Andrew N. Bortvin
AU  - Daniel Ariad
AU  - Avery Davis Bell
AU  - Rajiv C. McCoy
TI  - Strict adherence to Mendel’s First Law across a large sample of human sperm genomes
AID  - 10.1101/2021.11.19.469261
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2021.11.19.469261
4099  - http://biorxiv.org/content/early/2022/01/09/2021.11.19.469261.short
4100  - http://biorxiv.org/content/early/2022/01/09/2021.11.19.469261.full
AB  - 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.Competing Interest StatementA.D.B. 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. A.D.B. was an occasional consultant for Ohana Biosciences between October 2019 and March 2020.