Differentiating mechanism from outcome for ancestry-assortative mating in admixed human populations.

Population genetic theory, and the empirical methods built upon it, often assume that individuals pair randomly for reproduction. However, natural populations frequently violate this assumption, which may potentially confound genome-wide association studies, selection scans, and demographic inference. Within several recently admixed human populations, empirical genetic studies have reported a correlation in global ancestry proportion between spouses, referred to as ancestry-assortative mating.

Incomplete reprogramming of DNA replication timing in induced pluripotent stem cells.

Induced pluripotent stem cells (iPSCs) are the foundation of cell therapy. Differences in gene expression, DNA methylation, and chromatin conformation, which could affect differentiation capacity, have been identified between iPSCs and embryonic stem cells (ESCs). Less is known about whether DNA replication timing, a process linked to both genome regulation and genome stability, is efficiently reprogrammed to the embryonic state.

Getting it right: Teaching undergraduate biology to undermine racial essentialism.

How we teach human genetics matters for social equity. The biology curriculum appears to be a crucial locus of intervention for either reinforcing or undermining students' racial essentialist views. The Mendelian genetic models dominating textbooks, particularly in combination with racially inflected language sometimes used when teaching about monogenic disorders, can increase middle and high school students' racial essentialism and opposition to policies to increase equity.

Incomplete Reprogramming of DNA Replication Timing in Induced Pluripotent Stem Cells.

Induced pluripotent stem cells (iPSC) are a widely used cell system and a foundation for cell therapy. Differences in gene expression, DNA methylation, and chromatin conformation, which have the potential to affect differentiation capacity, have been identified between iPSCs and embryonic stem cells (ESCs). Less is known about whether DNA replication timing - a process linked to both genome regulation and genome stability - is efficiently reprogrammed to the embryonic state.

Replication stress impairs chromosome segregation and preimplantation development in human embryos.

Human cleavage-stage embryos frequently acquire chromosomal aneuploidies during mitosis due to unknown mechanisms. Here, we show that S phase at the 1-cell stage shows replication fork stalling, low fork speed, and DNA synthesis extending into G2 phase. DNA damage foci consistent with collapsed replication forks, DSBs, and incomplete replication form in G2 in an ATR- and MRE11-dependent manner, followed by spontaneous chromosome breakage and segmental aneuploidies.

Telomere-to-telomere human DNA replication timing profiles.

The spatiotemporal organization of DNA replication produces a highly robust and reproducible replication timing profile. Sequencing-based methods for assaying replication timing genome-wide have become commonplace, but regions of high repeat content in the human genome have remained refractory to analysis. Here, we report the first nearly-gapless telomere-to-telomere replication timing profiles in human, using the T2T-CHM13 genome assembly and sequencing data for five cell lines.

High-throughput analysis of single human cells reveals the complex nature of DNA replication timing control.

DNA replication initiates from replication origins firing throughout S phase. Debate remains about whether origins are a fixed set of loci, or a loose agglomeration of potential sites used stochastically in individual cells, and about how consistent their firing time is. We develop an approach to profile DNA replication from whole-genome sequencing of thousands of single cells, which includes in silico flow cytometry, a method for discriminating replicating and non-replicating cells.

Cancer Mutational Processes Vary in Their Association with Replication Timing and Chromatin Accessibility.

Cancer somatic mutations are the product of multiple mutational and repair processes, both of which are tightly associated with DNA replication. Distinctive patterns of somatic mutation accumulation, termed mutational signatures, are indicative of processes sustained within tumors. However, the association of various mutational processes with replication timing (RT) remains an open question.

TIGER: inferring DNA replication timing from whole-genome sequence data.

Motivation: Genomic DNA replicates according to a reproducible spatiotemporal program, with some loci replicating early in S phase while others replicate late. Despite being a central cellular process, DNA replication timing studies have been limited in scale due to technical challenges.

Results: We present TIGER (Timing Inferred from Genome Replication), a computational approach for extracting DNA replication timing information from whole genome sequence data obtained from proliferating cell samples.

Genomic methods for measuring DNA replication dynamics.

Genomic DNA replicates according to a defined temporal program in which early-replicating loci are associated with open chromatin, higher gene density, and increased gene expression levels, while late-replicating loci tend to be heterochromatic and show higher rates of genomic instability. The ability to measure DNA replication dynamics at genome scale has proven crucial for understanding the mechanisms and cellular consequences of DNA replication timing. Several methods, such as quantification of nucleotide analog incorporation and DNA copy number analyses, can accurately reconstruct the genomic replication timing profiles of various species and cell types.

Next-Generation Sequencing Enables Spatiotemporal Resolution of Human Centromere Replication Timing.

Centromeres serve a critical function in preserving genome integrity across sequential cell divisions, by mediating symmetric chromosome segregation. The repetitive, heterochromatic nature of centromeres is thought to be inhibitory to DNA replication, but has also led to their underrepresentation in human reference genome assemblies. Consequently, centromeres have been excluded from genomic replication timing analyses, leaving their time of replication unresolved.

Mismatch repair prefers exons.

A new analysis of cancer genomes identifies a decrease in the mutation burden of exons, but not introns, as compared to expectation. This difference can be explained by preferential recruitment of the DNA mismatch repair machinery to a protein modification that marks exons.

Aging impairs double-strand break repair by homologous recombination in Drosophila germ cells.

Aging is characterized by genome instability, which contributes to cancer formation and cell lethality leading to organismal decline. The high levels of DNA double-strand breaks (DSBs) observed in old cells and premature aging syndromes are likely a primary source of genome instability, but the underlying cause of their formation is still unclear. DSBs might result from higher levels of damage or repair defects emerging with advancing age, but repair pathways in old organisms are still poorly understood.