[A dream of preventive medicine].

Multi-Cancer Early Detection is a highly popular topic, bringing the hope of being able to detect very early, non-symptomatic cancers and allowing more successful therapy. A major company in this space is GRAIL, which has attracted very significant financing and launched large-scale tests of its detection systems. However, the real clinical utility of these tests remains to be demonstrated, and fundamental issues are still pending.

[A modular approach to in vivo gene therapy].

In vivo inactivation of a deleterious gene has been achieved in a small trial, with excellent clinical results. Interestingly, the delivery and editing system is the same as in previous work on a different disease, and the new therapy required simply changing the guide RNA used to target the Cas9 nuclease. This modular approach could be extended to a number of other genetic diseases.

[Ancient DNA speaks].

Many human DNA sequences have been obtained from ancient remains dating back from several millennia. However, these have low coverage and may contain many errors; this has limited their usefulness for many analyses, in particular the search for Identical By Descent (IBD) segments that is very powerful for detection of kinship. A new method, using imputation from database data and sophisticated statistical analysis, proves able to detect IBD segments (and thus parenthood) in low-quality DNA sequences from individuals linked only by sixth degree parenthood, opening a whole new field of investigation using ancient DNA.

[Why did I get cancer?].

Two interesting papers explore the beliefs of individuals (general population, or cancer survivors) on the causes of cancer. They reveal a huge discrepancy between scientifically proven factors and spontaneous opinions, that consider "stress" as the major cause of cancer. This is understandable in terms of psychological needs, and must be taken into account in cancer information campaigns.

[What "look-alike" individuals tell us].

Rare unrelated individuals show striking resemblance, almost as high as monozygotic twins. Extensive genetic analysis of a set of such individuals shows that every couple shares a given allele at a large set of loci, enriched for "face genes". The similarity is limited to this set of loci, and the rest of the genome is quite diverse in these "look alike" individuals.

[The foetal exome revealed].

New developments in the analysis of maternal cell-free DNA now allow complete analysis of the foetal exome. This makes possible an important extension of the breadth of prenatal diagnostics but raises significant ethical questions.

[The secrets of variants].

Most sequence variants encountered in medical genetics are of unknown significance, and their interpretation is a major stumbling block. Building on the successful AlphaFold system, the DeepMind group at Google has built a tool that predicts the pathogenic potential of any substitution in the human proteome. This is a major achievement and will be an important asset in clinical genetics.

[Does cancer screening really save lives ?].

Systematic screening for specific cancers has been shown to reduce cancer-specific mortality, but has not demonstrated an effect on all-cause mortality. This paradox is due to minor but frequent risks of screening bearing on a large population, and also to the small beneficial effect expected even if screening is highly efficient. Upcoming multicancer detection approaches should allow a better detection of the effect (if any) of screening on all-cause mortality.

[DNA everywhere].

Advanced analysis of environmental DNA for diversity monitoring using deep sequencing reveals the presence of human DNA in many samples connected to human activity.Moreover, this DNA is in relatively good condition and can be used for genetic survey of populations and even individuals. This opens many interesting scientific opportunities but also raises serious privacy issues.

[Everything about germinal mutations in vertebrates].

Mutations in the germline are an essential component of evolution. Current DNA sequencing systems allow quantification of these mutations through full genome sequencing of father/mother/child trios. A recent paper reports such a large-scale study spanning 68 vertebrate species, and establishes important features of the mutation process.

[New, more expensive - Not necessarily better].

The prices of new oncology drugs are frequently above 100,000 US dollars, and this does not generally correlate with significantly improved clinical efficacy. In the absence of effective regulation and of real competition, companies tend to charge « what the market can bear ». Regulatory intervention is required, notably at the EU level.

[End of a near-monopoly on DNA sequencing].

DNA sequencing costs have steadily decreased during the last decade, but the dominant technology (short-read sequencing, Illumina) has seen comparatively little competition after an initial flurry. This phase is now over, with serious competition involving both established and new companies as well as the growing importance of long-read sequencing. The hundred-dollar genome is in sight, and this will have a major impact on many fields of biology.

[Genetic legacy of the Black Death pandemic].

Genetic analysis of human populations before and after the great plague pandemic in the late Middle Ages reveals immune-related loci at which specific alleles have been selected because they conferred (partial) resistance to the pathogen. Some of these alleles are associated with susceptibility to present-day immune diseases, illustrating the complex interplay between genes, environment and the immune system.

[The birth of a gene].

The availability of an extensive set of vertebrate genome sequences, together with large-scale transcriptome studies, has allowed the discovery of numerous non-canonical ORFs (usually quite short) with evidence of transcription, translation and functional involvement. Orthologs for these ORFs can be detected in many vertebrates, and the time of appearance of a functional mini-gene can be ascertained. Some of these have appeared quite recently in evolution and have already very specific expression patterns in humans.

[A long-awaited - but prohibitively expensive - therapy].

After many years of development, a gene therapy for haemophilia B has demonstrated effectiveness and durability, at least over a time span of three years. It has just been approved (as Hemgenix®) by the FDA in the USA and by the EMA in the EU. However, the multimillion price tag of this treatment is a serious problem for healthcare systems and for patients, and raises a number of thorny issues about marketing practices of the pharmaceutical industry.

[Multiple loci account for human height].

The combination of 281 GWAS studies for adult height leads to the identification of 12,111 SNP in 7,209 loci that together account for essentially all SNP heritability for this trait: there is no longer any significant "missing heritability", and these loci appear to be functionally relevant. This work is a model for future studies on the genetic determinants of complex diseases.

[Life expectancy and Covid: Setting the record straight].

Life expectancy (LE) is an objective and highly reliable marker for events affecting demography. Analysing LE changes during the Covid pandemic shows widely different situations in a sample of 29 countries, highlighting comparatively efficient management in most Western European countries, in contrast to catastrophic results in Eastern Europe and in the United States. Loss of LE is also inversely correlated with vaccination uptake, confirming the efficacy of vaccines at the population level.

[Dog breeds and behaviour].

It is commonly believed that a dog's breed predicts its behaviour. A 2019 paper seemed to confirm this, but had some serious limitations. An extensive new study shows that, in fact, breed is not a good predictor of behaviour at the individual level, and has only a weak influence on average characteristics.

[Silent - but not neutral!].

An ingenious system for generating thousands of point mutations in yeast genes and measuring their effect on fitness shows convincingly that, for the chosen subset of representative non-essential genes, silent mutations have as much effect on fitness as missense mutations. In other words, silent mutations are not neutral, at least under these conditions. This result has important implications for evolutionary biology.

[Somatic mutations and longevity].

New approaches allow precise measurement of somatic mutations in tissues. Applied to a diverse set of mammals, these methods show that somatic mutation load increases with age (as expected) but reaches similar levels near the end of life for animals with extremely different longevity. This is an important result that has many repercussions on concepts of aging and of evolution of longevity.

[Human genome: The end of the beginning].

Two decades after its original publication, a new human genome sequence has just been published. Far from being an incremental improvement, it is at last really complete, covering each chromosome from one end to the other, with full elucidation of repeated sequences and an extremely low error rate. This is a major advance that tremendously increases our knowledge of our genome and will lead to important scientific and clinical developments.

[Mammoth "de-extinction", a "Colossal" hoax?].

Reports of a mammoth cloning project on-going under George Church's supervision appear periodically in the press. Close examination of the available evidence indicates that there is indeed such a project (carried out in a company called "Colossal"), but the aim is actually to modify the Asian elephant's genome so that the resulting animal displays some significant cold-adaptation traits, could theoretically be reintroduced into Siberia, and would then (also theoretically) modify the biotope towards its initial state of a steppe rather than a tundra. This endeavour seems largely unfeasible, but it may trigger important methodological advances that probably explain its ability to attract significant capital investment.

[Dogs, wolves and genes].

The most significant polymorphism associated with dog size occurs in the region of the IGF1 gene and concerns a single base change in a neighbouring lncRNA. The "small" (C) allele of this SNP is mostly found in small modern breeds and canids (foxes, coyotes, jackals) while the "large" (T) dominates in wolves and large dogs. However, the small allele is also present at low level in ancient wolves and is shown to represent the ancestral allele in canids, which has been recently selected in small dog breeds obtained by human selection.