Annual Review of Genetics

Within the life cycle of a living organism, another life cycle exists for the selfish genome inhabitants, which are called transposable elements (TEs). These mobile sequences invade, duplicate, amplify, and diversify within a genome, increasing the genome's size and generating new mutations. Cells act to defend their genome, but rather than permanently destroying TEs, they use chromatin-level repression and epigenetic inheritance to silence TE activity. This level of silencing is ephemeral and reversible, leading to a dynamic equilibrium between TE suppression and reactivation within a host genome...

Over more than fifty years, I have studied how the logic that controls and integrates cell function is built into the dynamic architecture of living cells. I worked with a succession of exceptionally talented students and postdocs, and we discovered that the bacterial cell is controlled by an integrated genetic circuit in which transcriptional and translational controls are interwoven with the three-dimensional deployment of key regulatory and morphological proteins. Caulobacter 's interconnected genetic regulatory network includes logic that regulates sets of genes expressed at specific times in the cell cycle and mechanisms that synchronize the advancement of the core cyclical circuit with chromosome replication and cytokinesis...

Spermatogenesis is a complex differentiation process coordinated spatiotemporally across and along seminiferous tubules. Cellular heterogeneity has made it challenging to obtain stage-specific molecular profiles of germ and somatic cells using bulk transcriptomic analyses. This has limited our ability to understand regulation of spermatogenesis and to integrate knowledge from model organisms to humans. The recent advancement of single-cell RNA-sequencing (scRNA-seq) technologies provides insights into the cell type diversity and molecular signatures in the testis...

Human accelerated regions (HARs) are the fastest-evolving sequences in the human genome. When HARs were discovered in 2006, their function was mysterious due to scant annotation of the noncoding genome. Diverse technologies, from transgenic animals to machine learning, have consistently shown that HARs function as gene regulatory enhancers with significant enrichment in neurodevelopment. It is now possible to quantitatively measure the enhancer activity of thousands of HARs in parallel and model how each nucleotide contributes to gene expression...

Scalable sequence-function studies have enabled the systematic analysis and cataloging of hundreds of thousands of coding and noncoding genetic variants in the human genome. This has improved clinical variant interpretation and provided insights into the molecular, biophysical, and cellular effects of genetic variants at an astonishing scale and resolution across the spectrum of allele frequencies. In this review, we explore current applications and prospects for the field and outline the principles underlying scalable functional assay design, with a focus on the study of single-nucleotide coding and noncoding variants...

Recent advances in genomics have revealed a wide spectrum of genetic variants associated with neurodevelopmental disorders at an unprecedented scale. An increasing number of studies have consistently identified mutations-both inherited and de novo-impacting the function of specific brain circuits. This suggests that, during brain development, alterations in distinct neural circuits, cell types, or broad regulatory pathways ultimately shaping synapses might be a dysfunctional process underlying these disorders...

Kinetochores are molecular machines that power chromosome segregation during the mitotic and meiotic cell divisions of all eukaryotes. Aristotle explains how we think we have knowledge of a thing only when we have grasped its cause. In our case, to gain understanding of the kinetochore, the four causes correspond to questions that we must ask: ( a ) What are the constituent parts, ( b ) how does it assemble, ( c ) what is the structure and arrangement, and ( d ) what is the function? Here we outline the current blueprint for the assembly of a kinetochore, how functions are mapped onto this architecture, and how this is shaped by the underlying pericentromeric chromatin...

In bacteria, transcription and translation take place in the same cellular compartment. Therefore, a messenger RNA can be translated as it is being transcribed, a process known as transcription-translation coupling. This process was already recognized at the dawn of molecular biology, yet the interplay between the two key players, the RNA polymerase and ribosome, remains elusive. Genetic data indicate that an RNA sequence can be translated shortly after it has been transcribed. The closer both processes are in time, the less accessible the RNA sequence is between the RNA polymerase and ribosome...

Meiosis, a key process in the creation of haploid gametes, is a complex cellular division incorporating unique timing and intricate chromosome dynamics. Abnormalities in this elaborate dance can lead to the production of aneuploid gametes, i.e., eggs containing an incorrect number of chromosomes, many of which cannot generate a viable pregnancy. For many decades, research has been attempting to address why this process is notoriously error prone in humans compared to many other organisms. Rapidly developing technologies, access to new clinical material, and a mounting public infertility crisis have kept the field both active and quickly evolving...

Animal species present relatively high levels of gene conservation, and yet they display a great variety of cell type and tissue phenotypes. These diverse phenotypes are mainly specified through differential gene usage, which relies on several mechanisms. Two of the most relevant mechanisms are regulated gene transcription, usually referred to as gene expression (rGE), and regulated alternative splicing (rAS). Several works have addressed how either rGE or rAS contributes to phenotypic diversity throughout evolution, but a back-to-back comparison between the two molecular mechanisms, specifically highlighting both their common regulatory principles and unique properties, is still missing...

DNA polymerase θ (Pol θ) is a DNA repair enzyme widely conserved in animals and plants. Pol θ uses short DNA sequence homologies to initiate repair of double-strand breaks by theta-mediated end joining. The DNA polymerase domain of Pol θ is at the C terminus and is connected to an N-terminal DNA helicase-like domain by a central linker. Pol θ is crucial for maintenance of damaged genomes during development, protects DNA against extensive deletions, and limits loss of heterozygosity...

The initiation, progression, and relapse of cancers often result from mutations occurring within somatic cells. Consequently, processes that elevate mutation rates accelerate carcinogenesis and hinder the development of long-lasting therapeutics. Recent sequencing of human cancer genomes has identified patterns of mutations, termed mutation signatures, many of which correspond to specific environmentally induced and endogenous mutation processes. Some of the most frequently observed mutation signatures are caused by dysregulated activity of APOBECs, which deaminate cytidines in single-stranded DNA at specific sequence motifs causing C-to-T and C-to-G substitutions...

Various stem cells in the body are tasked with maintaining tissue homeostasis throughout the life of an organism and thus must be resilient to intrinsic and extrinsic challenges such as infection and injury. Crucial to these challenges is genome maintenance because a high mutational load and persistent DNA lesions impact the production of essential gene products at proper levels and compromise optimal stem cell renewal and differentiation. Genome maintenance requires a robust and well-regulated DNA damage response suited to maintaining specific niches and tissues...

Though cell size varies between different cells and across species, the nuclear-to-cytoplasmic (N/C) ratio is largely maintained across species and within cell types. A cell maintains a relatively constant N/C ratio by coupling DNA content, nuclear size, and cell size. We explore how cells couple cell division and growth to DNA content. In some cases, cells use DNA as a molecular yardstick to control the availability of cell cycle regulators. In other cases, DNA sets a limit for biosynthetic capacity. Developmentally programmed variations in the N/C ratio for a given cell type suggest that a specific N/C ratio is required to respond to given physiological demands...

The discovery of biased histone inheritance in asymmetrically dividing Drosophila melanogaster male germline stem cells demonstrates one means to produce two distinct daughter cells with identical genetic material. This inspired further studies in different systems, which revealed that this phenomenon may be a widespread mechanism to introduce cellular diversity. While the extent of asymmetric histone inheritance could vary among systems, this phenomenon is proposed to occur in three steps: first, establishment of histone asymmetry between sister chromatids during DNA replication; second, recognition of sister chromatids carrying asymmetric histone information during mitosis; and third, execution of this asymmetry in the resulting daughter cells...

Since the identification of sickle cell trait as a heritable form of resistance to malaria, candidate gene studies, linkage analysis paired with sequencing, and genome-wide association (GWA) studies have revealed many examples of genetic resistance and susceptibility to infectious diseases. GWA studies enabled the identification of many common variants associated with small shifts in susceptibility to infectious diseases. This is exemplified by multiple loci associated with leprosy, malaria, HIV, tuberculosis, and coronavirus disease 2019 (COVID-19), which illuminate genetic architecture and implicate pathways underlying pathophysiology...

Autophagy, a lysosome-mediated degradation process evolutionarily conserved from yeast to mammals, is essential for maintaining cellular homeostasis and combating diverse cellular stresses. Autophagy involves de novo synthesis of a double-membrane autophagosome, sequestration of selected cellular contents, and subsequent delivery of sequestrated contents to the vacuole (in yeasts and plants) or to lysosomes (in animal cells) for degradation and recycling. Genetic studies in unicellular and multicellular model organisms have systematically revealed the molecular machinery, regulation, and function of autophagy in physiological settings...

Gametogenesis is a conserved developmental program whereby a diploid progenitor cell differentiates into haploid gametes, the precursors for sexually reproducing organisms. In addition to ploidy reduction and extensive organelle remodeling, gametogenesis naturally rejuvenates the ensuing gametes, leading to resetting of life span. Excitingly, ectopic expression of the gametogenesis-specific transcription factor Ndt80 is sufficient to extend life span in mitotically dividing budding yeast, suggesting that meiotic rejuvenation pathways can be repurposed outside of their natural context...

The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis...

Repeat-enriched genomic regions evolve rapidly and yet support strictly conserved functions like faithful chromosome transmission and the preservation of genome integrity. The leading resolution to this paradox is that DNA repeat-packaging proteins evolve adaptively to mitigate deleterious changes in DNA repeat copy number, sequence, and organization. Exciting new research has tested this model of coevolution by engineering evolutionary mismatches between adaptively evolving chromatin proteins of one species and the DNA repeats of a close relative...