Biology subjects

Bloom, J. S.

Publications and source records attributed to Bloom, J. S..

5 recordsLinked to original sources

bioRxiv2018

The genetic basis of mutation rate variation in yeast

Mutations are the root source of genetic variation and underlie the process of evolution. Although the rates at which mutations occur vary considerably between species, little is known about differences within species, or the genetic and molecular basis of these differences. Here we leveraged the power of the yeast Saccharomyces cerevisiae as a model system to uncover natural genetic variants that underlie variation in mutation rate. We developed a high-throughput fluctuation assay and used it to quantify mutation rates in natural yeast isolates and in 1040 segregant progeny from a cross between BY, a lab strain, and RM, a wine strain. We observed that mutation rate varies among yeast strains and is highly heritable (H2=0.46). We performed linkage mapping in the segregants and identified four quantitative trait loci (QTLs) underlying mutation rate variation in the cross. We fine-mapped two QTLs to the underlying causal genes, RAD5 and MKT1, that contribute to mutation rate variation. These genes also underlie sensitivity to the DNA damaging agents 4NQO and MMS, suggesting a connection between spontaneous mutation rate and mutagen sensitivity.

genetics↗

bioRxiv2018

Analysis of the genetic basis of height in large Jewish nuclear families

Despite intensive study, most genetic factors that contribute to variation in human height remain undiscovered. We conducted a family-based linkage study of height in a unique cohort of very large nuclear families from a founder (Jewish) population. This design allowed for increased power to detect linkage, compared to previous family-based studies. We identified loci that together explain an estimated 6% of the variance in height. We showed that these loci are not tagging known common variants associated with height. Rather, we suggest that the observed signals arise from variants with large effects that are rare globally but elevated in frequency in the Jewish population.

genetics↗

bioRxiv2017

Genetics of trans-regulatory variation in gene expression

Heritable variation in gene expression provides a critical bridge between differences in genome sequence and the biology of many traits, including common human diseases. However, the sources of most regulatory genetic variation remain unknown. Here, we used transcriptome profiling in 1,012 yeast segregants to map the genetic basis of variation in gene expression with high statistical power. We identified expression quantitative trait loci (eQTL) that together account for over 70% of the total genetic contribution to variation in mRNA levels, allowing us to examine the sources of regulatory variation comprehensively. We found that variation in the expression of a typical gene has a complex genetic architecture involving multiple eQTL. We also detected hundreds of eQTL pairs with significant non-additive interactions in an unbiased genome-wide scan. Although most genes were influenced by a local eQTL located close to the gene, most expression variation arose from distant, trans-acting eQTL located far from their target genes. Nearly all distant eQTL clustered at 102 \"hotspot\" locations, some of which influenced the expression of thousands of genes. Hotspot regions were enriched for transcription factor genes and altered expression of their target genes though both direct and indirect mechanisms. Many local eQTL had no detectable effects on the expression of other genes in trans. These results reveal the complexity of genetic influences on transcriptome variation in unprecedented depth and detail.

genetics↗

bioRxiv2017

Highly parallel genome variant engineering with CRISPR/Cas9 in eukaryotic cells

Direct measurement of functional effects of DNA sequence variants throughout a genome is a major challenge. We developed a method that uses CRISPR/Cas9 to engineer many specific variants of interest in parallel in the budding yeast Saccharomyces cerevisiae, and to screen them for functional effects. We used the method to examine the functional consequences of premature termination codons (PTCs) at different locations within all annotated essential genes in yeast. We found that most PTCs were highly deleterious unless they occurred close to the C-terminal end and did not interrupt an annotated protein domain. Surprisingly, we discovered that some putatively essential genes are dispensable, while others have large dispensable regions. This approach can be used to profile the effects of large classes of variants in a high-throughput manner.

genomics↗

bioRxiv2017

Genetic Variation In Adaptability And Pleiotropy In Budding Yeast

Evolution can favor organisms that are more adaptable, provided that genetic variation in adaptability exists. Here, we quantify this variation among 230 offspring of a cross between diverged yeast strains. We measure the adaptability of each offspring genotype, defined as its average rate of adaptation in a specific environmental condition, and analyze the heritability, predictability, and genetic basis of this trait. We find that initial genotype strongly affects adaptability and can alter the genetic basis of future evolution. Initial genotype also affects the pleiotropic consequences of adaptation for fitness in a different environment. This genetic variation in adaptability and pleiotropy is largely determined by initial fitness, according to a rule of declining adaptability with increasing initial fitness, but several individual QTLs also have a significant idiosyncratic role. Our results demonstrate that both adaptability and pleiotropy are complex traits, with extensive heritable differences arising from naturally occurring variation.

evolutionary biology↗