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List of candidate genes for the European population and the values of the significant statistics observed (p-value

We studiedDrosophila melanogasterpopulations from Europe (the Netherlands and France) and Africa (Rwanda and Zambia) to uncover genetic evidence of adaptation to cold. We present here four lines of evidence for genes involved in cold adaptation from four perspectives: (1) the frequency of SNPs at genes previously known to be associated with chill-coma recovery time (CCRT), startle reflex (SR), and resistance to starvation stress (RSS) vary along environmental gradients and therefore among populations; (2) SNPs of genes that correlate significantly with latitude and altitude in African and European populations overlap with SNPs that correlate with a latitudinal cline from North America; (3) at the genome-wide level, the top candidate genes are enriched in gene ontology (GO) terms that are related to cold tolerance; (4) GO enriched terms from North American clinal genes overlap significantly with those from Africa and Europe. Each SNP was tested in 10 independent runs ofBayenv2, using the median Bayes factors to ascertain candidate genes. None of the candidate genes were found close to the breakpoints of cosmopolitan inversions, and only four candidate genes were linked to QTLs related to CCRT. To overcome the limitation that we used only four populations to test correlations with environmental gradients, we performed simulations to estimate the power of our approach for detecting selection. Based on our results we propose a novel network of genes that is involved in cold adaptation.

Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. Denovodominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation ( NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies.