The contribution of evolutionarily volatile promoters to molecular phenotypes and human trait variation

BACKGROUND: Promoters are sites of transcription initiation that harbour a high concentration of phenotype-associated genetic variation. The evolutionary gain and loss of promoters between species (collectively, termed turnover) is pervasive across mammalian genomes and may play a prominent role in driving human phenotypic diversity. RESULTS: We classified human promoters by their evolutionary history during the divergence of mouse and human lineages from a common ancestor. This defined conserved, human-inserted and mouse-deleted promoters, and a class of functional-turnover promoters that align between species but are only active in humans. We show that promoters of all evolutionary categories are hotspots for substitution and often, insertion mutations. Loci with a history of insertion and deletion continue that mode of evolution within contemporary humans. The presence of an evolutionary volatile promoter within a gene is associated with increased expression variance between individuals, but only in the case of human-inserted and mouse-deleted promoters does that correspond to an enrichment of promoter-proximal genetic effects. Despite the enrichment of these molecular quantitative trait loci (QTL) at evolutionarily volatile promoters, this does not translate into a corresponding enrichment of phenotypic traits mapping to these loci. CONCLUSIONS: Promoter turnover is pervasive in the human genome, and these promoters are rich in molecularly quantifiable but phenotypically inconsequential variation in gene expression. However, since evolutionarily volatile promoters show evidence of selection, coupled with high mutation rates and enrichment of QTLs, this implicates them as a source of evolutionary innovation and phenotypic variation, albeit with a high background of selectively neutral expression variation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-022-02634-w

COMPLEMENT FACTOR B IS A DETERMINANT OF BOTH METABOLIC AND CARDIOVASCULAR FEATURES OF METABOLIC SYNDROME

CFB (complement factor B) is elevated in adipose tissue and serum from patients with type 2 diabetes mellitus and cardiovascular disease, but the causal relationship to disease pathogenesis is unclear. Cfb is also elevated in adipose tissue and serum of the spontaneously hypertensive rat, a well-characterized model of metabolic syndrome. To establish the role of CFB in metabolic syndrome, we knocked out the Cfb gene in the spontaneously hypertensive rat. Cfb−/− rats showed improved glucose tolerance and insulin sensitivity, redistribution of visceral to subcutaneous fat, increased adipocyte mitochondrial respiration, and marked changes in gene expression. Cfb−/− rats also had lower blood pressure, increased ejection fraction and fractional shortening, and reduced left ventricular mass. These changes in metabolism and gene expression, in adipose tissue and left ventricle, suggest new adipose tissue-intrinsic and blood pressure-independent mechanisms for insulin resistance and cardiac hypertrophy in the spontaneously hypertensive rat. In silico analysis of the human CFB locus revealed 2 cis-regulated expression quantitative trait loci for CFB expression significantly associated with visceral fat, circulating triglycerides and hypertension in genome-wide association studies. Together, these data demonstrate a key role for CFB in the development of spontaneously hypertensive rat metabolic syndrome phenotypes and of related traits in humans and indicate the potential for CFB as a novel target for treatment of cardiometabolic disease

Lagging strand replication shapes the mutational landscape of the genome 

The origin of mutations is central to understanding evolution and of key relevance to health. Variation occurs non-randomly across the genome, and mechanisms for this remain to be defined. Here we report that the 5' ends of Okazaki fragments have significantly increased levels of nucleotide substitution, indicating a replicative origin for such mutations. Using a novel method, emRiboSeq, we map the genome-wide contribution of polymerases, and show that despite Okazaki fragment processing, DNA synthesized by error-prone polymerase-alpha (Pol-alpha) is retained in vivo, comprising ~1.5% of the mature genome. We propose that DNA-binding proteins that rapidly re-associate post-replication act as partial barriers to Pol-delta-mediated displacement of Pol-alpha-synthesized DNA, resulting in incorporation of such Pol-alpha tracts and increased mutation rates at specific sites. We observe a mutational cost to chromatin and regulatory protein binding, resulting in mutation hotspots at regulatory elements, with signatures of this process detectable in both yeast and humans.Taylor, Martin; Kemp, Harriet; Marion de Procé, Sophie; Reijns, Martin; Ding, James; Jackson, Andrew. (2015). Lagging strand replication shapes the mutational landscape of the genome, [dataset]. University of Edinburgh. MRC Institute of Genetics and Molecular Medicine. MRC Human Genetics Unit. http://dx.doi.org/10.7488/ds/204