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Reposted by Kelley Harris

The American Journal of Human Genetics @ajhgnews.bsky.social · Aug 13

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📄Estimation of demography and mutation rates from one million haploid genomes
🧑‍🤝‍🧑 @jgschraiber.bsky.social @jeffspence.github.io @docedge.bsky.social

Estimation of demography and mutation rates from one million haploid genomes

Samples of millions of genomes provide substantial information about recent demography and mutation, but standard population-genetic methods make assumptions not met in these data. We introduce DR EVI...

www.cell.com

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Kelley Harris @kelleyharris.bsky.social · Jun 2

Amazing, congratulations!!

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Kelley Harris @kelleyharris.bsky.social · May 21

To close, I’ll highlight is that our model gives a general prediction of germline mutation rate as a function of generation time. When trio-based estimates aren’t available, this model may perform better than old phylogenetic estimates. www.nature.com/articles/nrg...

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Kelley Harris @kelleyharris.bsky.social · May 21

We did utilize the same data generated by Wang, et al. but looked at a different aspect of the data to reach the same conclusion, which even holds when looking only at offspring of younger mothers and replicates in an independent aye-aye dataset.

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Kelley Harris @kelleyharris.bsky.social · May 21

Consistent with prior phasing results, we estimated that most species have a higher paternal than maternal mutation rate. However, aye-aye was the exception, corroborating the recent finding of extraordinary maternal bias in the offspring of aged aye-aye mothers! journals.plos.org/plosbiology/...

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Kelley Harris @kelleyharris.bsky.social · May 21

For example, since the human maternal mutation rate per year is about 1/3 of the paternal mutation rate, a 3-to-1 weighted average of paternal and maternal age has a higher correlation with trio mutation load than either the paternal or maternal age alone.

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Kelley Harris @kelleyharris.bsky.social · May 21

To regress the total mutation rate against average parental age, we realized that we should find the weighted average of maternal and paternal age that has the highest correlation with mutation rate. This weighting is an estimate of the ratio of maternal to paternal age effects!

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Kelley Harris @kelleyharris.bsky.social · May 21

We thought a lot about how to regress mutation rate against parental age. Paternal and maternal age effects are usually inferred using just phased mutations, but since only about 1/3 of mutations can be phased to a parent in short-read trios, this throws away a lot of data.

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Kelley Harris @kelleyharris.bsky.social · May 21

We think that this main theoretical result will be very useful for interpreting and predicting mutation rate variation in multicellular species. I also want to highlight a few of the paper’s “side results” that we think may be just as useful to the community.

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Kelley Harris @kelleyharris.bsky.social · May 21

To explain these results, we show that selection against a mutator allele increasing the mutation rate per year in the germ cells is likely strongest in species with long generation times, since the allele will have more time to create extra mutations during each generation.

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Kelley Harris @kelleyharris.bsky.social · May 21

Consistent with prior work, the mutation rate per generation is highest in long-lived species with small effective population sizes. However, the opposite is true of the mutation rate per year in the germ cell lineages after puberty! (aye-aye outlier discussed more later in this thread)

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Kelley Harris @kelleyharris.bsky.social · May 21

We meta-analyzed variation in germline mutation rates among species and reproductive ages in order to disentangle changes molecular parameters like DNA repair from variation caused by demographic parameters like spermatogonial and oocyte aging.

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Kelley Harris @kelleyharris.bsky.social · May 21

Species with long lifespans tend to have low effective population sizes because they reproduce slowly and use many environmental resources. This could lessen the effectiveness of weak selection to avoid a small number of germline mutations per generation. www.annualreviews.org/content/jour...

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Kelley Harris @kelleyharris.bsky.social · May 21

We wanted to understand whether species with longer lifespans have better or worse DNA repair than species with short lifespans. Longevity appears to be associated with lower somatic mutation rates, but some population genetic theory predicts the opposite trend in the germline 🤔

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Kelley Harris @kelleyharris.bsky.social · May 21

. @pnas.org just published the final version of our manuscript on how generation time and effective population size interact to shape vertebrate germline mutation rates, led by Luke Zhu and Annabel Beichman: www.pnas.org/doi/10.1073/...

PNAS

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans...

www.pnas.org

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Kelley Harris @kelleyharris.bsky.social · May 20

Whoops, used the wrong handle to tag @aaronquinlan.bsky.social above!

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Kelley Harris @kelleyharris.bsky.social · May 20

We’ve released this simple, versatile tool as an R package and we hope that others will try it out as a simple aid for the interpretation of mutational signature differences among tumors. All feedback is appreciated! github.com/sfhart33/mut...

GitHub - sfhart33/mutspecdist: R package for Aggregate Mutation Spectrum Distance (AMSD) method

R package for Aggregate Mutation Spectrum Distance (AMSD) method - sfhart33/mutspecdist

github.com

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Kelley Harris @kelleyharris.bsky.social · May 20

Many of these associations have been previously reported, but the AMSD provides a simple, unified framework for ranking their significance and easily assessing which tumors appear to have etiologies that differ the most dramatically among populations.

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Kelley Harris @kelleyharris.bsky.social · May 20

We found that PolE hypermutation is most common in endometrial and colorectal tumors from people of East Asian descent, lung cancers from African Americans have more tobacco-associated mutations, and melanomas from Europeans have a higher UV-associated mutation load.

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Kelley Harris @kelleyharris.bsky.social · May 20

Next, we tested whether genetic ancestry was associated with human tumor mutation spectra. The AMSD revealed a suite of associations between ancestry and mutation load, which could reflect both genetic differences in cancer susceptibility and social determinants of health.

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Kelley Harris @kelleyharris.bsky.social · May 20

We first used the AMSD to reassess a previous study reporting that many carcinogens failed to cause distinctive mutational signatures in a mouse experiment. We found that many of these carcinogens still significantly perturbed the composition of the mutation spectrum.

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Kelley Harris @kelleyharris.bsky.social · May 20

We now generalize the AMSD to test which exposures appear to perturb tumor mutation spectra. If this test finds that two groups of tumors have statistically indistinguishable mutation spectra, that saves us overintepreting small differences in their mutational signature profiles.

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Kelley Harris @kelleyharris.bsky.social · May 20

We previously developed the AMSD with Tom Sasani and @aaronquinlan to test whether two groups of sequences have significantly different mutation spectra. We successfully used it to identify a germline mutator allele in the BXD mice: elifesciences.org/articles/89096

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Kelley Harris @kelleyharris.bsky.social · May 20

Mutational signature analysis is a very powerful tool for decomposing tumor mutation burdens into different endogenous and exogenous exposures, but when underlying mutation counts are sparse, it is not easy to tell which differences between signature profiles are meaningful.

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Kelley Harris @kelleyharris.bsky.social · May 20

If you’ve ever wondered about the statistical significance of differences among mutational signature profiles, check out our new Aggregate Mutation Spectrum Distance (AMSD) preprint co-led by Sam Hart and @alisonfeder.bsky.social with @nalcala.bsky.social www.biorxiv.org/cgi/content/...

A signature-agnostic test for differences between tumor mutation spectra reveals carcinogen and ancestry effects

Mutational signatures contain valuable information about the mutational processes shaping cancer genomes. However, despite dozens of tools to identify signatures in cancer samples, there is not an est...

www.biorxiv.org

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