Isaac García

📣 Paper alert!

I am delighted that our paper exploring the impact of Neanderthal-derived variants on the activity of a disease-associated craniofacial enhancer has been published in Development today!
journals.biologists.com/dev/article/...

Huge thanks to my supervisors @r-rahbari.bsky.social & @hilarycmartin.bsky.social, our collaborators, and most importantly, the @genomicsengland.bsky.social participants for making this research possible! ✨✨

Origins of germline mutations and bioinformatic ascertainment of parental postzygotic mutations A. Classification of germline mutations according to mutation timing. Postzygotic mutations (PZMs, rows 1–3, bottom to top) can affect both somatic and germline lineages if they occur before segregation of somatic and germline fates (i.e., early PZMs), or be restricted to the germline tissue if they arise in germline progenitors (i.e., germline-confined PZMs). For both categories, the earlier a mutation occurs, the larger the fraction of future gametes that will carry it. In contrast, de novo mutations (DNMs, top row) arise later in life during gametogenesis and affect only a subset of germline progenitors or single gametes. Gametes are represented with sperm cells, however, germline mutations can arise in both the male and female germline. B. Approximate proportions of somatic and germline cells carrying each type of mutation, with the right-hand scale indicating the likelihood of transmission to offspring. C. Overview of this study: analysis of trio WGS data for Mendelian inconsistencies supported by ≥1 ALT read, yielding 1,015 candidate early PZMs (cPZMs) in parents.

We developed a pipeline to detect these early mosaic mutations in @genomicsengland.bsky.social family trio genomes 👨‍💻🔍👪. They’re rare, but may help to explain otherwise unsolved rare disease cases and refine recurrence risk for families 🧬✨.

Landscape of parental postzygotic mutations in >11,000 rare disease trios Postzygotic mutations (PZMs) arising post-fertilisation, prior to primordial germ cell specification, may be subsequently inherited by both somatic and germ cells, causing somatic mosaicism in the par...

New preprint from another part of my PhD! 📝👇

Some mutations arise after fertilisation 🧬, so early they can appear in both a parent’s body and their germ cells.
By analysing family trio genomes 👪, we built one of the largest catalogues of these “hidden” inherited variants yet.

tinyurl.com/mvns2ytv

Common and rare genetic variants show network convergence for a majority of human traits While both common and rare variants contribute to the genetic etiology of complex traits, whether their impacts manifest through the same effector genes and molecular mechanisms is not well understood...

Interesting new @medrxivpreprint.bsky.social study, bearing on the interpretation of GWAS results: 
“Common and rare genetic variants show network convergence for a majority of human traits” 🧪🧬
www.medrxiv.org/content/10.1...

This package is a game changer for population genetics. You can do pretty much all of the “usual” analyses, in R, and at a super fast speed 😍😍😍

So thanks mainly Evie and Andrea for creating this for all of us!

New online! Making sense of the polygenicity of complex traits

Delighted that the 'flagship' manuscript on our @genesandhealth.bsky.social 44k exomes (British Pakistanis & Bangladeshis) is now preprinted. Great academic-industry collaboration. Lots of new associations (mostly additive, a few recessive) and new insights into homoz knockouts & drug discovery.

Check out the new pre-print from Luci! 👇🏾 Super cool work highlighting the discovery of a blood biomarker of IBD! 👀🧬🔬

All the nitty gritty details in the paper! Many thanks to everyone who was part of this journey, including all of the participants of the 100,000 Genomes project @genomicsengland.bsky.social

We report DNM rate and spectra differences between genetically inferred ancestral populations 🗺️🧬 and an association between smoking behaviour 🚬 and DNM rate.

An awesome collaboration between the @hilarycmartin.bsky.social @r-rahbari.bsky.social & @aylwyn-scally.bsky.social groups

The impact of ancestral, genetic, and environmental influences on germline de novo mutation rates and spectra - Nature Communications Here the authors analyze de novo mutations in >10,000 parent-offspring trios and find that ancestry and smoking independently associate with mutation rate, but that common genetic variants likely c...

It's finally out people ✅🗞️! Check out the final version of our work exploring factors influencing the germline mutation rate and spectra on ~10,000 WGS family trios 🧬👨‍👩‍👦!

www.nature.com/articles/s41...

Assessment of the variant prioritisation strategy for genomic newborn screening in the Generation Study Purpose Genomic sequencing offers the opportunity to screen for hundreds of rare genetic conditions with a single test. To minimise potential negative impact on families and clinical services, it is c...

Our preprint describing and assessing the variant prioritisation approach for genomic newborn screening in the Generation Study @genomicsengland.bsky.social is now on medRxiv www.medrxiv.org/content/10.1...

Illustration depicting the ways in which fungi can exchange genetic material with each other. Starship mediated HGT is confirmed experimentally in this preprint.

We did it! We caught Starship #transposons moving between #fungal species in the lab, including between species separated by ~100my. We think Starships are a mediator of HGT in fungi, akin to conjugative elements in bacteria. Check out the preprint. www.biorxiv.org/content/10.1...

Thrilled to share new work led by @jieyang437.bsky.social in the lab published today in @Nature. We find that Aspirin prevents metastasis by releasing T cells from immune suppression by platelet TXA2. @Cambridge_Uni @CRUKCamCentre rdcu.be/eci1U

Comparative analysis of human and mouse ovaries across age https://www.biorxiv.org/content/10.1101/2025.02.27.640481v1

I want to tell you a story about computers, creativity and art. (1/N) 🧵
Sydney Brenner once said in 2012 that “nobody has actually read the human genome. I mean, computers have processed the human genome, but we all know computers are stupid.”
(Summary of a talk I gave at the Sanger last week)

Pubmed

Contralateral cancers are an enigma: the unaffected organ is perfectly matched on exposures across life, yet despite this at older ages the risk of cancer in that organ is not much higher than a randomly selected organ from the same population. What can be happening? youtu.be/7rbsGpz9-XE

Whole-genome sequencing analysis of anthropometric traits in 672,976 individuals reveals convergence between rare and common genetic associations Genetic association studies have mostly focussed on common variants from genotyping arrays or rare protein-coding variants from exome sequencing. Here, we used whole-genome sequence (WGS) data in 672,...

Really excited to share our next population-scale WGS work preprint. Here, we analyse three anthropometric traits in nearly 700,000 individuals (discovery UKB ~450K, replication AoU). We show, for these traits, that common and rare variant heritability is convergent

www.biorxiv.org/content/10.1...

We finally have some well-powered whole-genome heritability estimates, including a quasi-behavioral trait (BMI). For height, ~89% of the heritability estimated to reside in common variants. For BMI and WHR, ~100% estimated in common variants.

www.biorxiv.org/content/10.1...

Significantly increased load of hereditary cancer–linked germline variants in infertile men AbstractSTUDY QUESTION. What is the comparative load and profile of hereditary cancer–linked germline variants in infertile compared to fertile men?SUMMARY

Interesting new paper on links between male infertility and increased cancer risk from Maris Laan:
academic.oup.com/hropen/advan...

Whole-genome sequencing analysis identifies rare, large-effect noncoding variants and regulatory regions associated with circulating protein levels Nature Genetics - Rare variant association analysis of plasma proteins using whole-genome sequencing data in 54,306 individuals in the UK Biobank demonstrates that combining both single-variant and...

Excited to finally share that our paper looking at the effect of rare non-coding variants using WGS on circulating protein levels in the UKB has been released in Nature Genetics @naturegenet.bsky.social! We now analyse the full 3,000 circulating proteins in all 50,000 individuals rdcu.be/ea16i

Should biology put complexity first? The dictum “Everything should be made as simple as possible, but no simpler” poses a problem for biology. How simply can it be told without doing damage to its complex nature? The answer might be foun...

Quantitative genetics is poorly understood by many biologists, and that's surely a failure in how it is taught. But teaching biology as 'fundamentally complex' seems like one of the least promising educational ideas since those 1970s schools that made lessons optional.
www.cell.com/cell-systems...

Intracellular competition shapes plasmid population dynamics Conflicts between levels of biological organization are central to evolution, from populations of multicellular organisms to selfish genetic elements in microbes. Plasmids are extrachromosomal, self-r...

I'm so happy that I can finally share the results of my first postdoc paper with @baym.lol!!! Turns out plasmids are an amazing system to study multi-scale evolution and we can track within-cell and between-cell dynamics!
(1/n) www.biorxiv.org/content/earl...

Ancient DNA HLA typing reveals significant shifts in frequency in Europe since the Neolithic - Scientific Reports Computational HLA typing has surged as a cost-effective strategy to uncover questions regarding the evolution of the HLA system, enabling immunogenic characterization from ancient DNA (aDNA) data. Nev...

Thrilled to share my 1st PhD's 1st publication at
@liigh-unam.bsky.social. Anecdotally it is also my 1st paper as corresponding author from my group / the "Paloegenomics and Evolutionary Biology". shorturl.at/VumOq Let us know what you think about it.

We are excited to announce a new faculty position here in Cambridge, for researchers in computational and/or theoretical biology, based jointly in Genetics and Mathematics. Come and join us! Happy to answer questions about research, teaching and working here. www.jobs.cam.ac.uk/job/50414/

Integrating the environmental and genetic architectures of aging and mortality - Nature Medicine Based on a systematic analysis of environmental exposures associated with aging and mortality in the UK Biobank, the relative contributions of such exposures and genetic risk for mortality and a range...

Our lifestyle and environmental exposures are the predominant influencers of healthy aging and premature mortality, compared with polygenic risk, in the first comprehensive assessment
www.nature.com/articles/s41...
open-access

Our thymus, a critical source and trainer of T cells, involutes with aging. 2 new studies find a growth factor (FGF21) that delays involution (in mouse models) and may be a way to rejuvenate our immune system and promote healthy aging in the future.