Amazing Science

An international research team led by the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, has for the first time successfully isolated ancient human DNA from a Paleolithic artefact: a pierced deer tooth discovered in Denisova Cave in southern Siberia. To preserve the integrity of the artefact, they developed a new, nondestructive method for isolating DNA from ancient bones and teeth. From the DNA retrieved they were able to reconstruct a precise genetic profile of the woman who used or wore the pendant, as well as of the deer from which the tooth was taken. Genetic dates obtained for the DNA from both the woman and the deer show that the pendant was made between 19,000 and 25,000 years ago. The tooth remains fully intact after analysis, providing testimony to a new era in ancient DNA research, in which it may become possible to directly identify the users of ornaments and tools produced in the deep past.

The team tested the influence of various chemicals on the surface structure of archaeological bone and tooth pieces and developed a non-destructive phosphate-based method for DNA extraction. “One could say we have created a washing machine for ancient artifacts within our clean laboratory," explains Elena Essel, the lead author of the study who developed the method. "By washing the artifacts at temperatures of up to 90°C, we are able to extract DNA from the wash waters, while keeping the artifacts intact.”

Immature sperm cells isolated from the caput epididymis harbor the most complex proteome of the three samples analyzed, comprising 6,045 proteins, including 1,284 (93.9%) of all proteins previously identified in independent studies of mouse caput epididymal sperm cells, thereby extending the proteomic annotation of this sperm population by an additional 4,761 proteins. However, scientists now identified a dramatic reduction in the number of proteins comprising the mature sperm proteome, with as many as 3,385 proteins apparently being lost from spermatozoa during their epididymal transit. Notably, while this proportional loss of 56% of the sperm proteome may appear at odds with accepted paradigms of sperm maturation, it nevertheless draws striking parallels to the 42% loss of the sperm proteome reported in the only other large-scale proteomic investigation of mouse epididymal spermatozoa by Skerget et al., 2015. Notwithstanding a substantial loss of proteins coincident with epididymal transit, cauda epididymal sperm cells retained a core proteome of 2,660 proteins in common with their caput epididymal sperm counterparts. This core proteome was supplemented by the addition of 264 proteins uniquely detected in NC cauda epididymal spermatozoa, a proportional gain of 9% of the total proteome. The proteome (2,924 proteins) of mature cauda epididymal sperm included 87.9% of the proteins (i.e., 1,062 proteins) identified by Skerget et al., 2015 in their proteomic study of mouse spermatozoa as well as an additional 1,999 proteins that were not previously characterized.

Like modern HIV, ancient human endogenous retroviruses (HERVs) had to insert their genetic material into their host’s genome to replicate.

Viruses insert their genomes into their hosts in the form of a provirus. There are around 30 different kinds of HERVs in people today, amounting to over 60,000 proviruses in the human genome.

They demonstrate the long history of the many pandemics humanity has been subjected to over the course of evolution.

Scientists think these viruses once widely infected the population, since they have become fixed in not only the human genome but also in chimpanzee, gorilla and other primate genomes. Research has demonstrated that HERV genes are active in diseased tissue, such as tumors, as well as during human embryonic development. But how active HERV genes are in healthy tissue was still largely unknown.

To answer this question, Aidan Burn, a Ph.D. candidate at Tufts University, and his colleagues decided to focus on one group of HERVs known as HML-2. This group is the most recently active of the HERVs, having gone extinct less than 5 million years ago. Even now, some of its proviruses within the human genome still retain the ability to make viral proteins.

The researchers examined the genetic material in a database containing over 14,000 donated tissue samples from all across the body. They looked for sequences that matched each HML-2 provirus in the genome and found 37 different HML-2 proviruses that were still active. All 54 tissue samples they analyzed had some evidence of activity of one or more of these proviruses. Furthermore, each tissue sample also contained genetic material from at least one provirus that could still produce viral proteins.

Role of HERVs in Human Health and Disease

The fact that thousands of pieces of ancient viruses still exist in the human genome and can even create protein has drawn a considerable amount of attention from researchers, particularly since related viruses still active today can cause breast cancer and AIDS-like disease in animals.

Whether the genetic remnants of human endogenous retroviruses can cause disease in people is still under study. Researchers have spotted virus-like particles from HML-2 in cancer cells, and the presence of HERV genetic material in diseased tissue has been associated with conditions such as Lou Gehrig’s disease, or amyotrophic lateral sclerosis, as well as multiple sclerosis and even schizophrenia.

The new study adds a new angle to these data by showing that HERV genes are present even in healthy tissue. This means that the presence of HERV RNA may not be enough to connect the virus to a disease. Importantly, it also means that HERV genes or proteins may no longer be good targets for drugs.

HERVs have been explored as a target for a number of potential drugs, including antiretroviral medication, antibodies for breast cancer and T-cell therapies for melanoma. Treatments using HERV genes as a cancer biomarker will also need to take into account their activity in healthy tissue. On the other hand, the study also suggests that HERVs could even be beneficial to people.

The most famous HERV embedded in human and animal genomes, syncytin, is a gene derived from an ancient retrovirus that plays an important role in the formation of the placenta.

Pregnancy in all mammals is dependent on the virus-derived protein coded in this gene. Similarly, mice, cats and sheep also found a way to use endogenous retroviruses to protect themselves against the original ancient virus that created them.

While these embedded viral genes are unable to use their host’s machinery to create a full virus, enough of their damaged pieces circulate in the body to interfere with the replication cycle of their ancestral virus if the host encounters it. Scientists theorize that one HERV may have played this protective role in people millions of years ago.

The study highlights a few more HERVs that could have been claimed or co-opted by the human body much more recently for this same purpose.

Epigenomic profiling has enabled large-scale identification of regulatory elements, yet we still lack a systematic mapping from any sequence or variant to regulatory activities. Researchers now address this challenge with Sei, a framework for integrating human genetics data with sequence information to discover the regulatory basis of traits and diseases. Sei learns a vocabulary of regulatory activities, called sequence classes, using a deep learning model that predicts 21,907 chromatin profiles across >1,300 cell lines and tissues.

Sequence classes provide a global classification and quantification of sequence and variant effects based on diverse regulatory activities, such as cell type-specific enhancer functions. These predictions are supported by tissue-specific expression, expression quantitative trait loci and evolutionary constraint data. Furthermore, sequence classes enable characterization of the tissue-specific, regulatory architecture of complex traits and generate mechanistic hypotheses for individual regulatory pathogenic mutations. Sei is provided as a resource to elucidate the regulatory basis of human health and disease. Sei is a new framework for integrating human genetics data with a sequence-based mapping of predicted regulatory activities to elucidate mechanisms contributing to complex traits and diseases.

Deciphering how regulatory functions are encoded in genomic sequences is a major challenge in understanding how genome variation links to phenotypic traits. Cell type-specific regulatory activities encoded in elements such as promoters, enhancers and boundary elements are critical to defining the complex expression programs essential for multicellular organisms. Most disease-associated variants from genome-wide association studies (GWAS) are located in noncoding regions1, yet without knowing how changes in sequence affect regulatory activities, we cannot predict the impact of these variants and uncover the regulatory mechanisms contributing to complex diseases and traits.

Substantial progress has been made in the experimental profiling and integrative analysis of epigenomic marks, such as histone marks and DNA accessibility, across a wide range of tissues and cell types2,3,4. At the same time, deep learning sequence modeling techniques have been successfully applied to learn sequence features predictive of transcription factor (TF) binding and histone modifications5,6,7,8,9,10,11. These models are powerful tools for inferring the impact of sequence variation at the chromatin level—for example, whether a variant increases or decreases C/EBPβ binding. However, we continue to lack an integrative view of sequence regulatory activities, including all major aspects of cis-regulatory functions, such as tissue-specific or broad enhancer and promoter activities. This limits our ability to interpret the integrated effects of all chromatin-level perturbations caused by genomic variants and determine their impact on human health and diseases.

The researchers address this challenge by creating a global map for sequence regulatory activity based on a new deep learning-based framework called Sei. This framework introduces a sequence model that predicts 21,907 publicly available chromatin profiles—the broadest set to date—and uses the model to quantitatively characterize regulatory activities for any sequence with a vocabulary we call sequence classes. Sequence classes cover diverse types of regulatory activities, such as promoter or cell type-specific enhancer activity, across the whole genome by integrating sequence-based predictions from histone marks, TFs and chromatin accessibility across a wide range of cell types. Importantly, sequence classes can be used to both classify and quantify the regulatory activities of any sequence based on predictions made by the deep learning sequence model, thereby allowing any mutation to be quantified by its impact (for example, increase, decrease or no change) on cell type-specific regulatory activities.

Thus, Sei enables an interpretable and systematic integration of sequence-based regulatory activity predictions with human genetics data to elucidate the regulatory basis of complex traits and diseases. We applied our framework to characterize disease- and trait-associated regulatory disruptions in GWAS data based on a nonoverlapping partitioning of heritability by regulatory activities. Moreover, we applied variant effect prediction at the sequence class-level to interpret cell type-specific regulatory mechanisms for individual disease mutations and differentiate between gain-of-function (GoF) and loss-of-function (LoF) regulatory mutations.

The Sei framework in its current form is provided as a resource for systematically classifying and scoring any sequence and variant with sequence classes, additionally providing the Sei model predictions for the 21,907 chromatin profiles underlying the sequence classes. The framework can be run using the code available at https://github.com/FunctionLab/sei-framework; a user-friendly web server is available at hb.flatironinstitute.org/sei.

A new high-throughput genomic array offers an unprecedented look into the mouse epigenome, giving researchers an in-depth view into the basis of health and disease in a vital model organism.

The array was developed by scientists at Van Andel Institute, Children's Hospital of Philadelphia and University of Pennsylvania in collaboration with Illumina and FOXO Technologies. It contains more than 296,000 probes that represent the diversity of murine DNA methylation biology.

"DNA methylation is one of the pillars of epigenetics research," said VAI Associate Professor Hui Shen, Ph.D., co-corresponding author of the study that describes the array, which published today in Cell Genomics. "This array gives scientists around the world a powerful new tool to understand the role of methylation in normal processes and in diseases like cancer and many others."

Since the 1980s, it has become clear that epigenetics plays a role in virtually every aspect of health and disease. This revelation has given rise to a growing field that has illuminated vital insights into myriad diseases such as cancer, which is now known to be driven by both genetic and epigenetic errors. The new array includes markers for an extensive list of biological features, including genomic imprinting, aging, cancer, variably methylated regions, germ cell development, tissue specificity, X-linked probes, and epigenetic clocks.

Development of the array was led by Shen, VAI Professor Peter W. Laird, Ph.D., co-corresponding author of the study, and Children's Hospital of Philadelphia and University of Pennsylvania Assistant Professor Wanding Zhou, Ph.D., a former postdoctoral fellow in the Laird and Shen labs. "We learned many lessons from the current and previous generations of human arrays and have improved the overall quality of probe design," said Zhou, who also is a corresponding author of the study. "For example, we optimized the probe selection to cover the diverse biology of DNA methylation in mice while minimizing the chance of probe misuse and artifacts. The array also features probe sets that will enable comparative epigenome analysis between humans and mice as well as among other rodents."

The array allows scientists to interrogate methylation more quickly and more deeply than previous methods. It enabled the team to develop a rich atlas of DNA methylation profiles across more than 1,200 samples, representing diverse cell types, strains and pathologies. Before now, DNA methylation data were available but not centralized. The atlas, made possible by the array, offers scientists a central repository for this critical information. Additionally, the array has been implemented in the popular bioinformatics tool SeSAMe.

New research transforms our understanding of the circumstances and timing of the domestication of chickens, their spread across Asia into the west, and reveals the changing way in which they were perceived in societies over the past 3,500 years.

Experts have found that an association with rice farming likely started a process that has led to chickens becoming one of the world's most numerous animals. They have also found evidence that chickens were initially regarded as exotica, and only several centuries later used as a source of 'food'.

Previous efforts have claimed that chickens were domesticated up to 10,000 years ago in China, Southeast Asia, or India, and that chickens were present in Europe over 7,000 years ago. The new studies show this is wrong, and that the driving force behind chicken domestication was the arrival of dry rice farming into southeast Asia where their wild ancestor, the red jungle fowl, lived. Dry rice farming acted as a magnet drawing wild jungle fowl down from the trees, and kickstarting a closer relationship between people and the jungle fowl that resulted in chickens.

Parts of the human genome now available to study for the first time are important for understanding genetic diseases, human diversity, and evolution.

The first truly complete sequence of a human genome, covering each chromosome from end to end with no gaps and unprecedented accuracy, is now accessible through the UCSC Genome Browser and is described in six papers published today (March 31, 2022) in Science.

Since the first working draft of a human genome sequence was assembled at UC Santa Cruz in 2000, genomics research has led to enormous advances in our understanding of human biology and disease. Nevertheless, crucial regions accounting for some 8% of the human genome have remained hidden from scientists for over 20 years due to the limitations of DNA sequencing technologies.

Karen Miga, assistant professor of biomolecular engineering at UC Santa Cruz, and Adam Phillippy at the National Human Genome Research Institute (NHGRI) organized an international team of scientists—the Telomere-to-Telomere (T2T) Consortium—to fill in the missing pieces. Their efforts have now paid off.

A tiny parasitoid wasp species is revealed in a new study to comprise at least 16 different species, identical in appearance but genetically distinct.

Some undiscovered species are hiding right under our noses. Ormyrus labotus, a tiny parasitoid wasp known to science since 1843, has long been considered a generalist, laying its eggs in more than 65 different species of other insects. But a new study in Insect Systematics and Diversity suggests wasps currently called Ormyrus labotus are actually at least 16 different species, identical in appearance but genetically distinct, each parasitizing a narrower range of host species. Shown here are wasp specimens collected by researchers at the University of Iowa that all matched the description of Ormyrus labotus. But, by combining genetic analysis with data on the wasps’ physical attributes and ecological factors, the researchers say these wasps all belong to separate species—a finding that underlines the importance of seeking out the world’s “hidden diversity.”

Researchers  have discovered new types of cells in the brain of developing flies thanks to a new method that creates cell-type-specific genetic tools. The study, published in the journal Proceedings of the National Academy of Sciences (PNAS), combines single-cell sequencing data with a novel algorithm to identify pairs of genes that point to previously unknown cells in the brains of fruit flies.

Scales, spines, feathers and hair are examples of vertebrate skin appendages, which constitute a remarkably diverse group of micro-organs. Despite their natural multitude of forms, these appendages share early developmental processes at the embryonic stage. Two researchers from the University of Geneva (UNIGE) have discovered how to permanently transform the scales that normally cover the feet of chickens into feathers, by specifically modifying the expression of certain genes. These results, published in the journal Science Advances, open new perspectives for studying mechanisms that have enabled radical evolutionary transitions in form among species.

The skin of terrestrial vertebrates is adorned with diverse keratinized appendages, such as hair, feathers, and scales. Despite the diversity of forms within and among species, the embryonic development of skin appendages typically begins in a very similar way. Indeed, all of these structures develop from cells that produce a localized thickening on the skin surface and express particular genes. One of these genes, called Sonic hedgehog (Shh), controls a signaling pathway - a communication system that allows the transmission of messages within and between cells. Shh signalling is involved in the development of diverse structures, including the neural tube, limb buds and skin appendages.

A common ancestor

The laboratory of Michel Milinkovitch, professor in the Department of Genetics and Evolution at the Faculty of Science of the UNIGE, is interested in the physical and biological processes that generate the diversity of skin appendages in vertebrates. In particular, his group has previously demonstrated that hair, feathers and scales are homologous structures inherited from a reptilian common ancestor.

Feathers of the chicken embryo are used by scientists as a model system to understand skin appendage development. While it is known that certain breeds of chickens, such as the ‘Brahma’ and ‘Sablepoot’ varieties, exhibit feathered legs and dorsal foot surfaces, the genetic determinism of this trait is not fully  understood.

A transient modification for a permanent change

As the signaling pathways responsible for this transformation have not been fully determined, Michel Milinkovitch’s group investigated the potential role of the Shh pathway. “We used the classic technique of ‘egg candling’, in which a powerful torch illuminates blood vessels on the inside of the eggshell. This allowed us to precisely treat chicken embryos with a molecule that specifically activates the Shh pathway, injected directly into the bloodstream,’’ explains Rory Cooper, a post-doctoral researcher in Michel Milinkovitch’s laboratory and co-author of the study.

The two scientists observed that this single stage-specific treatment is sufficient to trigger the formation of abundant juvenile down-type feathers, in areas that would normally be covered with scales. Remarkably, these experimentally-induced feathers are comparable to those covering the rest of the body, as they are regenerative and are subsequently and autonomously replaced by adult feathers.

After comparison with embryos injected with a ‘control’ solution (without the active molecule), RNA sequencing analysis showed that the Shh pathway is both immediately and persistently activated following injection of the molecule. This confirms that activation of the Shh pathway underlies the conversion of scales into feathers.

‘‘Our results indicate that an evolutionary leap - from scales to feathers - does not require large changes in genome composition or expression. Instead, a transient change in expression of one gene, Shh, can produce a cascade of developmental events leading to the formation of feathers instead of scales,’’ says Michel Milinkovitch. This research, initially focused on the study of the development of scales and feathers, therefore has important implications for understanding the evolutionary mechanisms generating the enormous diversity of animal forms observed in nature.

Scientists have made groundbreaking progress in characterizing the fraction of human DNA that varies between individuals.

For more than 20 years, scientists have relied on the human reference genome, a consensus genetic sequence, as a standard against which to compare other genetic data. Used in countless studies, the reference genome has made it possible to identify genes implicated in specific diseases and trace the evolution of human traits, among other things. But it has always been a flawed tool. One of its biggest problems is that about 70 percent of its data came from a single man of predominantly African-European background whose DNA was sequenced during the Human Genome Project, the first effort to capture all of a person's DNA. As a result, it can tell us little about the 0.2 to one percent of genetic sequence that makes each of the seven billion people on this planet different from each other, creating an inherent bias in biomedical data believed to be responsible for some of the health disparities affecting patients today. Many genetic variants found in non-European populations, for instance, aren't represented in the reference genome at all.

For years, researchers have called for a resource more inclusive of human diversity with which to diagnose diseases and guide medical treatments. Now scientists with the Human Pangenome Reference Consortium have made groundbreaking progress in characterizing the fraction of human DNA that varies between individuals. As they recently published in Nature, they have assembled genomic sequences of 47 people from around the world into a so-called pangenome in which more than 99 percent of each sequence is rendered with high accuracy. Layered upon each other, these sequences revealed nearly 120 million DNA base pairs that were previously unseen. While it's still a work in progress, the pangenome is public and can be used by scientists around the world as a new standard human genome reference, says The Rockefeller University's Erich D. Jarvis, one of the primary investigators.

"This complex genomic collection represents significantly more accurate human genetic diversity than has ever been captured before," he says. "With a greater breadth and depth of genetic data at their disposal, and greater quality of genome assemblies, researchers can refine their understanding of the link between genes and disease traits, and accelerate clinical research."

Sourcing diversity

A research team led by André Marques at the Max Planck Institute for Plant Breeding Research in Cologne, Germany, has uncovered the profound effects of an atypical mode of chromosome arrangement on genome organization and evolution. Their findings are published in the journal Cell.

In each individual cell in our body, our DNA, the molecule carrying the instructions for development and growth, is packaged together with proteins into structures called chromosomes. Full sets of chromosomes together constitute the genome, the entire genetic information of an organism. In most organisms, including us, chromosomes appear as X-shaped structures when they are captured in their condensed, duplicated states in preparation for cell division. Indeed, these structures may be among the most iconic in all of science. The X shape is due to a constricted region called the centromere that serves to connect sister chromatids, which are the identical copies formed by the DNA replication of a chromosome.

Most studied organisms are 'monocentric', meaning that centromeres are restricted to a single region on each chromosome. Several animal and plant organisms, however, show a very different centromere organization: instead of one solitary constriction as in the classic X-shaped chromosomes, chromosomes in these organisms harbor multiple centromeres that are arranged in a line from one end of a sister chromatid to the other. Thus, these chromosomes lack a primary constriction and the X shape, and species with such chromosomes are known as 'holocentric', from the ancient Greek word hólos meaning 'whole'.

A new study led by André Marques from the Max Planck Institute for Plant Breeding Research in Cologne, Germany, now reveals the striking effects of this non-classical mode of chromosome organization on genome architecture and evolution. To determine how holocentricity affects the genome, Marques and his team used highly accurate DNA sequencing technology to decode the genomes of three closely related holocentric beak-sedges, grass-like flowering plants found worldwide that are often the first conquerors of new habitats. For reference, the team also decoded the genome of their most closely related monocentric relative. Thus, comparing the holocentric beak-sedges with their monocentric relative allowed the authors to attribute any differences they observed to the effects of holocentricity.

Their analysis reveals striking differences in genome organization and chromosome behavior in holocentric organisms. They found that centromere function is distributed across hundreds of small centromere domains in holocentric chromosomes. While in monocentric organisms, genes are largely concentrated distant from centromeres and the regions immediately around them, in holocentric species they are uniformly distributed over the whole length of chromosomes. Further, in monocentric species chromosomes are known to engage in a high degree of intermingling with each other during cell division, a property which appears to play a role in regulating gene expression. Notably, these long-range interactions were sharply diminished in the beak-sedges with holocentromeres. Thus, holocentricity fundamentally affects genome organization as well as how chromosomes behave during cell division.

In holocentric organisms, almost any given chromosomal fragment will harbor a centromere and will thus have proper centromere function, which is not true for monocentric species. In this way, holocentromeres have been thought to stabilize chromosomal fragments and fusions and thus promote rapid genome evolution, or the ability of an organism to make prompt, wholesale changes to its DNA. In one of the beak-sedges they analyzed, Marques and his team could show that chromosome fusions facilitated by holocentromeres allowed this species to maintain the same chromosome number even after quadruplication of the entire genome. In another of their analyzed beak-sedges, a species with only two chromosomes, the lowest of any plant, holocentricity was found to be responsible for the dramatic reduction in chromosome number. Thus, holocentric chromosomes may allow the formation of news species through rapid evolution at genome-level.

The human genome is littered with "selfish genetic elements," which do not seem to benefit their hosts, but instead seek only to propagate themselves. Selfish genetic elements can wreak havoc by, for instance, distorting sex ratios, impairing fertility, causing harmful mutations, and even potentially causing population extinction.

Biologists at the University of Rochester, including Amanda Larracuente, an associate professor of biology, and Daven Presgraves, a University Dean's Professor of Biology, have for the first time used population genomics to shed light on the evolution and consequences of a selfish genetic element known as Segregation Distorter (SD). In a paper published in the journal eLife, the researchers report that SD has caused dramatic changes in chromosome organization and genetic diversity.

Pigs are valuable large animal models for biomedical and genetic research, but insights into the tissue- and cell-type-specific transcriptome and heterogeneity remain limited. By leveraging single-cell RNA sequencing, scientists now generated a multiple-organ single-cell transcriptomic map containing over 200,000 pig cells from 20 tissues/organs. They were able to comprehensively characterize the heterogeneity of cells in tissues and to identify 234 cell clusters, representing 58 major cell types. In-depth integrative analysis of endothelial cells reveals a high degree of heterogeneity. They also identified several functionally distinct endothelial cell phenotypes, including an endothelial to mesenchymal transition subtype in adipose tissues. Intercellular communication analysis predicts tissue- and cell type-specific crosstalk between endothelial cells and other cell types through the VEGF, PDGF, TGF-β, and BMP pathways. Regulon analysis of single-cell transcriptome of microglia in pig and 12 other species further identifies MEF2C as an evolutionally conserved regulon in the microglia.

This important work describes the landscape of single-cell transcriptomes within diverse pig organs and identifies the heterogeneity of endothelial cells and evolutionally conserved regulon in microglia.

The cancer patients saw their tumors disappear after the treatment, and have been cancer-free for two years.

A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.

CONCLUSIONS

Mismatch repair–deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772. opens in new tab.)

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and aging.

Scientists now performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. They found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans, although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined—including variation of around 30-fold in lifespan and around 40,000-fold in body mass—the somatic mutation burden at the end of lifespan varied only by a factor of around 3.

These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in aging.

Scientists have developed a powerful, inclusive new tool for genomic research that boosts efforts to develop more precise treatments for many diseases by leveraging a better representation of the genetic diversity of people around the world.

The new tool will allow researchers to compare natural variations in our genes against genome sequences collected from a diverse group of people. Until now, scientists have compared these variations with a "reference genome" primarily sequenced from a few volunteers (~70% from one person) living near laboratories involved in the Human Genome Project almost 20 years ago. This represented genomes from a small number of people in a small number of countries.

The new software tool, called "Giraffe," enables the use of a reference point that is far more diverse and inclusive. Instead of relying on a single reference genome, Giraffe uses a "pangenome" that incorporates information about genome sequences from people around the world. This will give scientists a much more global perspective and help them understand why diseases often strike certain groups disproportionately.

"A major advantage of Giraffe is that it enables fast and sensitive comparison of short-read human genome sequences to a pangenome, which is essential for the widespread use of reference graphs that reduce bias in the human genome reference," said researcher Stephen S. Rich, PhD, of the University of Virginia School of Medicine's Center for Public Health Genomics. "Since the current effort in genomics is to move from a European-Caucasian base to a global representation, Giraffe can better define genetic variation in non-white populations and, as a result, have a major impact on precision medicine and application to understanding the genetic risk of disease."