Breaking Down Meiosis During meiosis, gametes (egg and sperm cells) are formed, each containing half of the parent’s genetic material. During this process, homologous chromosomes exchange segments of DNA, a process known as crossing-over. This recombination is essential for genetic diversity and proper chromosome movement. Recombination begins with programmed DNA double-stranded breaks (DSBs). Some breaks are repaired without crossover using the identical sister chromatid as a template, while others use the homologous chromosome, leading to genetic variation. Recent research shows that DSB repair is more error-prone than previously believed, contributing to genetic variation across generations. Notably, DSBs during meiosis result in new genetic changes in 1 in 4 sperm and 1 in 12 eggs. Researchers also discovered that DSBs are often concentrated in specific regions of the genome, known as “recombination hotspots.” A repaired DSB is significantly more likely to result in mutations, such as single base pair changes or structural variants, compared to areas without DSBs. The study also found that DSB repair is less accurate in males, correlating with a higher mutation rate observed in sperm.
This study highlights that the DNA break and repair process during meiosis is a major source of genetic change in the human germline. While meiotic recombination is critical for genetic diversity, it comes with an increased risk of introducing new DNA changes. While many DNA changes have little to no impact, some can have a significant impact on health and disease risk. n
REFERENCE: Hinch R, et al., Meiotic DNA breaks drive multifaceted mutagenesis in the human germ line. Science . [2023] 382(6674):eadh2531. Epub 2023 Dec 1. https://www.science.org/doi/10.1126/science.adh2531
AI Driven Discovery Every cell in an organism’s body contains a complete set of genetic instructions, but only certain genes are active in each cell. This precise control is essential for creating the diverse cells in each organism. Cis-regulatory elements (CREs) are DNA sequences that act like switches, determining which genes are turned on or off in particular cells. The human genome has many highly specific CREs, each with distinct features that target certain genes or cell types. Researchers are using AI to understand those features and design new CREs. Researchers selected hundreds of thousands of DNA sequences and cataloged their CRE activity in three different cell types. This data was used to train an AI model to find patterns and predict which specific features in CREs impact expression across different genes and cell types. The researchers used the model to design a platform called Computational Optimization of DNA Activity, or CODA, which creates synthetic CREs designed to target specific genes or cell types. When the synthetic CREs were tested on cells, researchers were surprised to find they were less likely to affect unintended cell types than naturally occurring CREs. Finally, the team tested the synthetic CREs on zebrafish and mice, showing genes could be regulated in brain or liver cells without affecting expression in the rest of the animal. This exciting breakthrough illustrates how AI can help discover the functions of complicated DNA sequences. Although more study is needed, synthetic CREs might also provide a way to treat disease through controlling gene expression. n REFERENCE: Gosai SJ, et al., Machine-guided design of cell-type-targeting cis-regulatory elements. Nature. [2024] 634:1211–1220 https://doi.org/10.1038/s41586-024-08070-z
A Nobel Prize 40 Years in the Making
Victor Ambros and Gary Ruvkun were awarded the 2024 Nobel Prize in
Physiology or Medicine for their groundbreaking work on microRNAs and gene expression, which they began in the 1980s. As post-doctoral fellows studying cell and tissue development in the roundworm C. elegans , they discovered that the gene lin-4 suppressed the expression of another gene, lin-14 . Years later, while leading their own research labs, they collaborated and uncovered the mechanism behind this interaction. They found that the lin-4 gene produces short RNA segments, just 22 bases long, which are not translated into proteins. These ultra-short RNA molecules, now known as microRNAs (miRNAs), have sequences complementary to the messenger (mRNA) of lin-14 , allowing them to bind and prevent the lin-14 mRNA from being translated into protein. This discovery explained how lin-4 regulates the expres- sion of lin-14 . Ruvkun’s subsequent discovery of another microRNA demonstrated that miRNAs are not unique to roundworms but are present in various animals. The molecule discovered by Ambros and Ruvkun was tiny, but the impact was large. Further research into microRNAs has discovered roles for these tiny sequences in many developmental and disease pathways. n REFERENCE: “The Nobel Prize in Physiology or Medicine 2024” The National Assembly at Karolinska Instituet. 18 December 2024. https://www.nobelprize.org/prizes/medicine/2024/press-release Accessed 14 January 2025. Press Release.
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