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Whole-genome sequencing in probing the meiotic recombination and aneuploidy of single sperm cells

Posted in Biological Networks, Gene Regulation and Evolution, Chemical Genetics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, tagged amplification, aneuploidy, chromosome, DNA, Genetic recombination, genome, Homologous chromosome, Meiosis, meiotic recombination, Multiple displacement amplification, sperm on February 6, 2013| 3 Comments »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Meiosis plays a crucial role in generating haploid gametes for sexual reproduction. In most organisms, the presence of crossovers between homologous chromosomes, in combination with connections between sister chromatids, creates a physical connection that ensures regular segregation of homologs at the first of the two meiotic divisions.

Abnormality in generating crossovers is the leading cause of miscarriage and birth defects. Crossovers also create new combinations of alleles, thus contributing to genetic diversity and evolution. Recent linkage disequilibrium and pedigree studies have shown that the distribution of recombination is highly uneven across the human genome, as in all studied organisms. Substantial recombination active regions are not conserved between humans and chimpanzees or among different human populations, suggesting that these regions are quickly evolving and might even be individual-specific. However, such variation in the human population would be masked by the population average, and resolution of this variation would require comparison of recombination genome-wide among many single genomes.

Whole-genome amplification (WGA) of single sperm cells was proposed decades ago to facilitate mapping recombination at the individual level. With the development of highthroughput genotyping technologies, whole–genome mapping of recombination events in single gametes of an individual is achievable and was recently demonstrated by performing WGA by multiple displacement amplification (MDA) on single sperm cells, followed by genotyping with DNA microarrays recently demonstrated by Wang et al.. However, due to the amplification bias and, consequently, insufficient marker density, the resolution of crossover locations has been limited to ~150 kb thus far. In addition, in their recent work, Wang et al. relied on prior knowledge of the chromosome-level haplotype information of the analyzed individual, which is experimentally inconvenient to obtain and is currently available for only a few individuals.

Meiotic recombination creates genetic diversity and ensures segregation of homologous chromosomes. Previous population analyses yielded results averaged among individuals and affected by evolutionary pressures. In this study 99 sperm from an Asian male was sequenced by using the newly developed amplification method—multiple annealing and looping-based amplification cycles—to phase the personal genome and map recombination events at high resolution, which are non-uniformly distributed across the genome in the absence of selection pressure. The paucity of recombination near transcription start sites observed in individual sperm indicates that such a phenomenon is intrinsic to the molecular mechanism of meiosis. Interestingly, a decreased crossover frequency combined with an increase of autosomal aneuploidy is observable on a global per-sperm basis.