Dataset Information

A familial, telomere-to-telomere reference for human de novo mutation and recombination from a four-generation pedigree.

ABSTRACT: Using five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5 de novo single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 de novo indels or structural variants (SVs) originating from tandem repeats, 7.7 centromeric de novo SVs and SNVs, and 12.4 de novo Y chromosome events per generation. STRs and VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations, documenting de novo SVs, and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 17% of de novo SNVs are postzygotic in origin with no paternal bias. We place all this variation in the context of a high-resolution recombination map (~3.5 kbp breakpoint resolution). We observe a strong maternal recombination bias (1.36 maternal:paternal ratio) with a consistent reduction in the number of crossovers with increasing paternal (r=0.85) and maternal (r=0.65) age. However, we observe no correlation between meiotic crossover locations and de novo SVs, arguing against non-allelic homologous recombination as a predominant mechanism. The use of multiple orthogonal technologies, near-telomere-to-telomere phased genome assemblies, and a multi-generation family to assess transmission has created the most comprehensive, publicly available "truth set" of all classes of genomic variants. The resource can be used to test and benchmark new algorithms and technologies to understand the most fundamental processes underlying human genetic variation.

SUBMITTER: Porubsky D

PROVIDER: S-EPMC11326147 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

A familial, telomere-to-telomere reference for human de novo mutation and recombination from a four-generation pedigree.

Porubsky David D Dashnow Harriet H Sasani Thomas A TA Logsdon Glennis A GA Hallast Pille P Noyes Michelle D MD Kronenberg Zev N ZN Mokveld Tom T Koundinya Nidhi N Nolan Cillian C Steely Cody J CJ Guarracino Andrea A Dolzhenko Egor E Harvey William T WT Rowell William J WJ Grigorev Kirill K Nicholas Thomas J TJ Oshima Keisuke K KK Lin Jiadong J Ebert Peter P Watkins W Scott WS Leung Tiffany Y TY Hanlon Vincent C T VCT McGee Sean S Pedersen Brent S BS Goldberg Michael E ME Happ Hannah C HC Jeong Hyeonsoo H Munson Katherine M KM Hoekzema Kendra K Chan Daniel D DD Wang Yanni Y Knuth Jordan J Garcia Gage H GH Fanslow Cairbre C Lambert Christine C Lee Charles C Smith Joshua D JD Levy Shawn S Mason Christopher E CE Garrison Erik E Lansdorp Peter M PM Neklason Deborah W DW Jorde Lynn B LB Quinlan Aaron R AR Eberle Michael A MA Eichler Evan E EE

bioRxiv : the preprint server for biology 20240805

Using five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5 de novo single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 de novo indels or structural variants (SVs) originating ...[more]

PMID: 39149261

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Project description:Hybridization between Saccharomyces cerevisiae and Saccharomyces eubayanus resulted in the emergence of S. pastorianus, a crucial yeast for lager fermentation. However, our understanding of hybridization success and hybrid vigor between these two species remains limited due to the scarcity of S. eubayanus parental strains. Here, we explore hybridization success and the impact of hybridization on fermentation performance and volatile compound profiles in newly formed lager hybrids. By selecting parental candidates spanning a diverse array of lineages from both species, we reveal that the Beer and PB-2 lineages exhibit high rates of hybridization success in S. cerevisiae and S. eubayanus, respectively. Polyploid hybrids were generated through a spontaneous diploid hybridization technique (rare-mating), revealing a prevalence of triploids and diploids over tetraploids. Despite the absence of heterosis in fermentative capacity, hybrids displayed phenotypic variability, notably influenced by maltotriose consumption. Interestingly, ploidy levels did not significantly correlate with fermentative capacity, although triploids exhibited greater phenotypic variability. The S. cerevisiae parental lineages primarily influenced volatile compound profiles, with significant differences in aroma production. Interestingly, hybrids emerging from the Beer S. cerevisiae parental lineages exhibited a volatile compound profile resembling the corresponding S. eubayanus parent. This pattern may result from the dominant inheritance of the S. eubayanus aroma profile, as suggested by the over-expression of genes related to alcohol metabolism and acetate synthesis in hybrids including the Beer S. cerevisiae lineage. Our findings suggest complex interactions between parental lineages and hybridization outcomes, highlighting the potential for creating yeasts with distinct brewing traits through hybridization strategies.ImportanceOur study investigates the principles of lager yeast hybridization between Saccharomyces cerevisiae and Saccharomyces eubayanus. This process gave rise to the lager yeast Saccharomyces pastorianus. By examining how these novel hybrids perform during fermentation and the aromas they produce, we uncover the genetic bases of brewing trait inheritance. We successfully generated polyploid hybrids using diverse strains and lineages from both parent species, predominantly triploids and diploids. Although these hybrids did not show improved fermentation capacity, they exhibited varied traits, especially in utilizing maltotriose, a key sugar in brewing. Remarkably, the aroma profiles of these hybrids were primarily influenced by the S. cerevisiae parent, with Beer lineage hybrids adopting aroma characteristics from their S. eubayanus parent. These insights reveal the complex genetic interactions in hybrid yeasts, opening new possibilities for crafting unique brewing yeasts with desirable traits.

Dataset Information

A familial, telomere-to-telomere reference for human de novo mutation and recombination from a four-generation pedigree.

Publications

A familial, telomere-to-telomere reference for human <i>de novo</i> mutation and recombination from a four-generation pedigree.

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