Lifespan of different species correlated with mutation rate of non-reproductive (somatic) cells. This research came out in 2022 but for some reason I only found out about it today. But it seems worth sharing as it seems a key insight into the nature of lifespan. Humans have 47 substitutions per year, while mice have 796 and live much shorter lives.

"To study somatic mutations across a diverse set of mammals, we isolated 208 individual intestinal crypts from 56 individuals across 16 species with a wide range of lifespans and body sizes: black-and-white colobus monkey, cat, cow, dog, ferret, giraffe, harbour porpoise, horse, human, lion, mouse, naked mole-rat, rabbit, rat, ring-tailed lemur, and tiger."

"We chose intestinal crypts for several reasons. First, they are histologically identifiable units that line the epithelium of the colon and small intestine and are amenable to laser microdissection. Second, human studies have confirmed that individual crypts become clonally derived from a single stem cell and show a linear accumulation of mutations with age, which enables the estimation of somatic mutation rates through genome sequencing of single crypts. Third, in most human crypts, most somatic mutations are caused by endogenous mutational processes common to other tissues, rather than by environmental mutagens."

"Across species, the mutational spectra showed clear similarities, with a dominance of cytosine-to-thymine (C>T) substitutions at CpG sites, as observed in human colon, but with considerable variation in the frequency of other substitution types."

"Across the 15 species with age information, we found that substitution rates per genome ranged from 47 substitutions per year in humans to 796 substitutions per year in mice, and indel rates from 2.5 to 158 indels per year, respectively."

"Indel", short for insertion/deletion, is a general term that may refer to any combination of insertions and deletions in DNA.

"To investigate the relationship between somatic mutation rates, lifespan and other life-history traits, we first estimated the lifespan of each species using survival curves. We used a large collection of mortality data from animals in zoos to minimize the effect of extrinsic mortality. We defined lifespan as the age at which 80% of individuals reaching adulthood have died, to reduce the effects of outliers and variable cohort sizes that affect maximum lifespan estimates. Notably, we found a tight anticorrelation between somatic mutation rates per year and lifespan across species. A log-log allometric regression yielded a strong linear anticorrelation between mutation rate per year and lifespan (fraction of inter-species variance explained = 0.85, P = 1 x 10^-6), with a slope close to and not significantly different from -1. This supports a simple model in which somatic mutation rates per year are inversely proportional to the lifespan of a species (rate is approximately equal to 1/lifespan), such that the number of somatic mutations per cell at the end of the lifespan (the end-of-lifespan burden) is similar in all species."

"To further study the relationship between somatic mutation rates and life-history variables, we used linear mixed-effects regression models. These models account for the hierarchical structure of the data (with multiple crypts per individual and multiple individuals per species), as well as the heteroscedasticity of somatic mutation rate estimates across species. Using these models, we estimated that the inverse of lifespan explained 82% of the inter-species variance in somatic substitution rates (rate = k/lifespan) (P = 2.9 x 10^-9), with the slope of this regression (k) representing the mean estimated end-of-lifespan burden across species (3,206.4 substitutions per genome per crypt, 95% confidence interval 2,683.9-3,728.9). Of note, despite uncertainty in the estimates of both somatic mutation rates and lifespans, and despite the diverse life histories of the species surveyed--including around 30-fold variation in lifespan and around 40,000-fold variation in body mass--the estimated mutation load per cell at the end of lifespan varied by only around threefold across species."

"Analogous results were obtained when repeating the analysis with estimates of the protein-coding mutation rate, which may be a better proxy for the functional effect of somatic mutations (85% of variance explained; end-of-lifespan burden: 31 coding substitutions per crypt)."

"Giraffe and naked mole-rat, for instance, have similar somatic mutation rates (99 and 93 substitutions per year, respectively), in line with their similar lifespans (80th percentiles: 24 and 25 years, respectively), despite a difference of around 23,000-fold in adult body mass. Similarly, cows, giraffes and horses weigh much more than an average human, and yet have somatic mutation rates that are several fold higher, in line with expectation from their lifespan but not their body mass."

Somatic mutation rates scale with lifespan across mammals

#discoveries #biology #genetics #dna #gwas #lifespan #longevity

"Comparative genomic study, the largest to date, includes genetic and phenotypic information of 57 species of mammals and identifies the greater stability of proteins as a common feature in the longest-living species".

So this research is all about convergent amino acid substitutions, and I had to do some work to understand what convergent amino acid substitutions are about. Basically, you can have a mutation in DNA, and that mutation, even if it is just a change to a single nucleotide, can change one of the amino acids in the protein the DNA encodes for. This change is what the word "substitution" refers to. The change can have no effect on the function of the protein, if the change is located somewhere that isn't related to the key parts that control the function of the protein. It also might have little effect, even if it is in one of the key parts, if the new amino acid is similar enough to the old one. It is also possible, however, for the change to have a very radical effect on the function of the protein.

The "convergent" part of that phrase has to do with the concept of convergent evolution. Convergent evolution is when two unrelated species evolve the same trait. For example, wings evolved in reptiles to form birds, and independently in mammals to form bats.

But the headline tells you this is about lifespan, so the question then becomes what all this has to do with longevity? Well, the way this research was structured was to find convergent amino acid substitutions in a variety of species, and compare those with the lifespan, and see which of those have longer or shorter lifespans than expected. This is different from previous genome-wide association studies (GWAS) that have focused on humans only.

They found 2,737 convergent amino acid substitutions in 2,004 genes where long-lived species have one amino acid and short-lived species have another. They further narrowed this down to 996 genes that they believe represent "true longevity signals" using statistical tests ("phylogenetic ANOVA test", whatever that is). The research paper has a lot of complex statistics that I didn't understand and can't summarize for you.

You may be wondering what the amino acid changes do? They think that they increase protein "stability", which is to say, proteins tend to "destabilize" with age and the convergent evolution of certain amino acid choices in long-lived species lead to those species having proteins that better resist this "destabilization".

They speculate what leads to this increased "stabilization" is "contacts in the hydrophobic core" and "a reduction in Van der Waals clashes".

The idea behind the "hydrophobic core" theory is that a protein will maintain a stable structure by constructing a shape such that there is a "center" created by a group of highly hydrophobic amino acids -- hydrophobic means they don't like water. Hydrophillic -- water-loving -- amino acids will be on the outside and will perform the function of the protein. Mutations that increase the stability of this "hydrophobic core" would, then, increase longevity, while mutations that decrease the stability of the "hydrophobic core" would decrease longevity.

Unfortunately I don't understand Van der Waals forces well enough to explain what "Van der Waals clashes" are. Van der Waals forces are forces that arise from quantum fluctuations in electron shells that result in fluctuating positive or negative electric forces that result in attraction or repulsion between parts of molecules that are very close to each other. They play a central role in organic chemistry, so I should probably learn about them.

The evolution of mammals reveals 2,000 new genes key to longevity in humans

#discoveries #evolution #proteome #genomics #gwas #longevity

"Using genome-wide association studies (GWAS) methodology to analyze whole-genome sequencing data of SARS-CoV-2 mutations and COVID-19 mortality data can identify highly pathogenic variants of the virus that should be flagged for containment."

"Using this biostatistical methodology, the researchers pinpointed a mutation in the variant known as P.1, or Gamma, as being linked to increased mortality and, potentially, greater transmissibility, higher infection rates, and increased pathogenicity before the P.1 variant had been identified."

"The researchers found one mutation -- at locus 25,088bp in the virus's genome -- that alters the spike protein and was linked to a significant increase in mortality in COVID-19 patients. The team flagged the variant with this mutation, which was later identified as part of P.1."

"We expect that this approach would work in similar scenarios involving other diseases, provided the quality of the data collected in public databases is sufficiently high."

Methodology from genome-wide association studies accurately flags more deadly SARS-CoV-2 variant

#discoveries #biology #genetics #gwas #coronavirus