A simplified model of admixture history between archaic and anatomically modern human populations.

<p>There is consensus that at least two independent gene-flow events occurred (solid arrows)—admixture from Neanderthals into an ancestral Eurasian population (solid blue) and from Denisovans into an ancestral Southeast Asia population (solid red). It is likely that additional instances of admixture occurred, explaining the variation in the percentage of archaic sequence across different global populations. These additional instances include a pulse of admixture from Neanderthals (dashed blue) and from Denisovans (dashed red) into an ancestral East Asian population. Alternatively, or in addition, global variation in archaic ancestry could be the result of admixture within human populations (dashed orange) diluting archaic sequence. Admixture from human populations may also have introduced sequence into archaic populations.</p

Patterns and characteristics of archaic sequence across the genome.

<p>(A) A representation of individual genomes from archaic and modern human populations. The modern human genomes (orange) are ordered by increasing levels of Neanderthal (blue) admixture percentage (approximate). Only Asian populations carry Denisovan (red) sequence. Some introgressed archaic segments are shared across populations, and some large regions of the genome are deserted of introgressed archaic sequence in all populations examined. (B) Large deserts may be a product of selection against deleterious archaic variants (gold stars) at those loci. Whether selection acted against a few strongly deleterious variants (top) or many weakly deleterious variants (bottom) remains uncertain. (C) Many segments of introgressed archaic sequence are found to carry variants (stars) that affect gene regulation and expression. Altering gene expression may affect downstream protein levels (e.g., immunological proteins) and could have provided a mechanism of rapid adaptation for admixed modern humans. (D) Putatively adaptive introgressed segments can be identified by examining the frequency of introgressed segments (blue dots) within a population and filtering for those that exceed a percentile cutoff (dashed black line).</p

Evolution and Genetic Architecture of Chromatin Accessibility and Function in Yeast

<div><p>Chromatin accessibility is an important functional genomics phenotype that influences transcription factor binding and gene expression. Genome-scale technologies allow chromatin accessibility to be mapped with high-resolution, facilitating detailed analyses into the genetic architecture and evolution of chromatin structure within and between species. We performed Formaldehyde-Assisted Isolation of Regulatory Elements sequencing (FAIRE-Seq) to map chromatin accessibility in two parental haploid yeast species, <i>Saccharomyces cerevisiae</i> and <i>Saccharomyces paradoxus</i> and their diploid hybrid. We show that although broad-scale characteristics of the chromatin landscape are well conserved between these species, accessibility is significantly different for 947 regions upstream of genes that are enriched for GO terms such as intracellular transport and protein localization exhibit. We also develop new statistical methods to investigate the genetic architecture of variation in chromatin accessibility between species, and find that <i>cis</i> effects are more common and of greater magnitude than <i>trans</i> effects. Interestingly, we find that <i>cis</i> and <i>trans</i> effects at individual genes are often negatively correlated, suggesting widespread compensatory evolution to stabilize levels of chromatin accessibility. Finally, we demonstrate that the relationship between chromatin accessibility and gene expression levels is complex, and a significant proportion of differences in chromatin accessibility might be functionally benign.</p></div

<i>Cis</i> and <i>trans</i> effects on chromatin accessibility.

<p>A. For each NFR, the relative chromatin accessibility in the haploid is plotted versus the relative chromatin accessibility in the diploid. NFRs with a significant <i>cis</i> effect are shown in pink. B. Reproduction of the plot from (A), but NFRs with a significant <i>trans</i> effect are shown in green. C. Violin plot showing the effect size distribution of <i>cis</i> and <i>trans</i> effects. D. Scatter plot of relative <i>cis</i> and <i>trans</i> effect sizes. Positive effects indicate higher accessibility in <i>S. cerevisiae</i> and negative effects indicate higher accessibility in <i>S. paradoxus</i>.</p

Patterns of chromatin accessibility within and between <i>S. cerevisiae</i> and <i>S. paradoxus</i>.

<p>A. Scatterplots of relative chromatin accessibility between <i>S. cerevisiae</i> strains DBVPG1373 and UWOPS05_217_3 (top), <i>S. cerevisiae</i> strain UWOPS05_217_3 and <i>S. paradoxus</i> strain CBS432 (middle), and <i>S. cerevisiae</i> strain DBVPG1373 and <i>S. paradoxus</i> strain CBS432 (bottom). Note, comparisons within and between species are shown as blue and light green, respectively. B. Heatmap representation of chromatin accessibility at all NFRs in <i>S. cerevisiae</i> strain UWOPS05_217_3 versus <i>S. paradoxus</i> strain CBS432. Each row is a NFR, and columns are the two biological replicates of <i>S. cerevisiae</i> strain UWOPS05_217_3 and <i>S. paradoxus</i> strain CBS432. Rows are sorted by average difference in signal at NFRs between <i>S. cerevisiae</i> and <i>S. paradoxus</i>. The far right column indicates if the difference in chromatin accessibility between species is significant (yellow rectangles).</p

Gene expression and chromatin accessibility.

<p>A. Boxplot of log₂(effect size) of both <i>cis</i> and <i>trans</i> effects for FAIRE (dark grey) and RNA (light grey). B. Barplot of the percentage of genes with significant <i>cis</i> effects in RNA that are downstream of NFRs with and without <i>cis</i> effects (left). Barplot of the percentage of genes with significant <i>trans</i> effects in RNA that are downstream of NFRs with and without <i>trans</i> effects (right). C. Scatterplot of the log₂(absolute value of the difference in chromatin accessibility between the two species) vs log₂(absolute value of the difference in expression between the two species. The red dot indicates data from the <i>MET10</i> gene, whose FAIRE-Seq and RNA data are shown in panel D. For clarity, the FAIRE-Seq data is only shown in a 100 bp window on either side of the NFR. FAIRE signal is shown in black, and RNA signal is shown in grey.</p

Motifs contributing to <i>cis</i> and <i>trans</i> effects.

<p>A. The odds ratio of observing a disrupted motif compared to a non-disrupted motif in NFRs with a significant <i>cis</i> effect. Odds ratios are shown for all motifs, as well as the two individual motifs (<i>GCN4</i> and <i>GZF3</i>) that were found to be significant by permutations (FDR = 0.10). B. Pattern of accessibility for four motifs found within <i>trans</i> effect NFRs that vary between <i>S. cerevisiae</i> and <i>S. paradoxus</i>.</p

Schematic of approach to detect <i>cis</i> and <i>trans</i> effects on chromatin accessibility.

<p>Top, an example of a NFR showing only a <i>trans</i> effect on chromatin accessibility. A <i>trans</i> effect is detected as a case where there is a difference in chromatin accessibility between the two parental haploid species, but there is no difference in chromatin accessibility between the two alleles in the hybrid. As shown above, this could be explained by a case where a nucleosome remodeler (shown as a hexagon) acts to evict nucleosomes and increase accessibility in <i>S. cerevisiae</i>, but a mutation in <i>S. paradoxus</i> has rendered it inactive and it is unable to evict the nucleosomes. In the diploid hybrid, the chromatin remodeler from <i>S. cerevisiae</i> is able to evict nucleosomes from both the <i>S. cerevisiae</i> and <i>S. paradoxus</i> chromosomes. Bottom, an example of a NFR showing only a <i>cis</i> effect on chromatin accessibility. A <i>cis</i> effect is detected as a difference between the accessibility detected between the two alleles in the diploid, and the lack of a <i>trans</i> effect is shown by the same difference being detected between the parental species. In this case, there has been a mutation at the NFR on the <i>S. cerevisiae</i> allele, leading to a difference in the number of nucleosomes binding in the region.</p

Supplemental Material for Jin et al., 2018

Genetics/2018/30102

Probability of being a case as a function of PC1 and PC2.

<p>Individuals (dots) are colored according to the logistic regression with β values scaled so that for this example an odds ratio (OR) of 5 for a distance of a fourth of the minimal and maximal values for each axis. In other words, individuals separated by a fourth of the PC distance will have an OR of 5 compared to each other. The probability of being a case is thus indicated by the color of each dot on a scale from 0.06 to 1, as indicated by the gradient (lower right corner).</p