Adam Phillippy

This was such a fun project.
Adam's thread on it is a great summary!

Credit to the two AMAZING students who led this work, Steven Solar and @prajnahebbar.bsky.social, as well as our long-time partners in acrocentric investigations 🕵 @leogdlima.bsky.social, Tamara Potapova, @thinks.lol, Evan Eichler, Mario Ventura, and Jen Gerton [21/21]

As Ohno said in his preface to Evolution by Gene Duplication, “natural selection merely modified, while redundancy created” [20/21]

Lesson learned: Repetitive regions of the genome, like the short arms of the acrocentrics, are prone to recombination and duplication. This makes them a pain to sequence, but also very dynamic. Natural selection can take advantage of that instability to effect rapid change [19/21]

This story is much better told in the paper, so I hope you’ll read it and come to appreciate the important role that acrocentric chromosomes have played in our evolution. The formerly “dark” regions of the genome have some interesting stories to tell [18/21]

To bring things full circle, the PHRs that mediated the diversification of FRG1 genes in our ancestors became the PHRs that today predispose our genomes to Robertsonian translocations. Oops, sometimes evolution be like that 😅 [17/21]

🤔 So, it seems all those FRG1 pseudogenes in the human genome are the remnants of an adaptive evolutionary event in our (very) distant ancestors that was mediated by the unique properties of the acrocentrics, including PHRs [16/21]

A similar story played out for FRG1, but much longer ago. This amplification has since died out in human/chimp/bonobo, leaving behind a raft of pseudogenes (>20 in human). However, gorilla and orangutan continue to maintain multiple coding copies with evidence of positive selection [15/21]

The unique properties of the acrocentrics allow the genes on them to rapidly amplify and recombine, perhaps enabling accelerated evolution, which the CDS tree for GGT appears to show for gorilla [14/21]

IGSF3-GGT still appears to be in the birth phase, with most copies maintaining an ORF. The hypothesis is that gorillas (or their recent ancestors) found the new IGSF3-GGT fusion useful, and it underwent diversifying positive selection [13/21]

We focused on two specific genes, a gorilla-specific fusion gene IGSF3-GGT and FRG1. These two genes are lovely examples of birth-and-death evolution. Intron trees show the IGSF3-GGT fusion was born ~9 Mya, while the initial FRG1 duplication dates to the ancestor of all apes ~26 Mya [12/21]

(4) Gorillas have 7 pairs of acrocentrics, but only 2 contain rDNA arrays. We discovered that the other 5 gorilla acrocentrics contain amplified *protein coding genes*, some of which show evidence of positive selection! [11/21]

a gorilla is sitting on the ground in a zoo cage . ALT: a gorilla is sitting on the ground in a zoo cage .

In addition to rDNAs, the human PHRs include megabases of segmentally duplicated pseudogenes. We identified one of these PHRs as the fusion site of (most) human Robertsonian translocations, but why do they exist in the first place? Seems like a bug, not a feature. Gorillas held the answer [10/21]

(3) In some cases, non-allelic recombination can maintain >99% sequence identity between *different* acrocentric chromosomes. We first saw this in human and named them “pseudo-homolog regions” (PHRs). We can now see that PHRs are a recurring feature of all the great ape acrocentrics [9/21]

This rapid turnover is partly due to the unique recombinational properties of the short arms. Meiotic crossovers appear repressed, but sequence exchange continues within and between chromosomes by other means such as non-allelic homologous recombination (NAHR), sister chromatid exchange, etc. [8/21]

(2) There is a huge amount of sequence turnover on the short arms, with all major ape lineages exhibiting strikingly different satellite patterns. Even chimp and bonobo (just 1–2 My diverged) have different characteristics (e.g. bonobo has a lot more HSat1) [7/21]

Did you ever wonder why human Chr9 has a huge block HSat3 near its centromere? That’s an ancient short arm you are looking at! Chr9 used to be acrocentric (and still is in gorilla and orangutan). An inversion in the ancestor of human/chimp/bonobo flipped the heterochromatin into the middle [6/21]

Assuming parsimony, there has been at least one acrocentric-to-metacentric conversion on each major branch of the great apes. The human Chr2 fusion is famous, but that is the only fusion in the great ape tree. Instead, short arm inversions have been the primary driver of karyotypic change [5/21]

(1) Over the past ~20 My of great ape evolution, there have been at least 6 whole-arm inversions that converted an acrocentric chromosome to a metacentric chromosome. Only orangutans have maintained the ancestral state of 10 acrocentrics, including rDNA on their Y chromosomes [4/21]

Finally finishing the short arms of the acrocentric chromosomes was my favorite part of the T2T-CHM13 project, and ever since I wanted to write a deeper paper on what we found. Since then we finished T2T genomes for all the apes and have kept digging. Here are some of the highlights... [3/21]

Basic intro: acrocentric chromosomes are the ones with asymmetric arms, with the centromere positioned more towards the tip (Greek άκρο) than the middle. In human, the short arms of these chromosomes are home to the 45S rDNA arrays and a whole mess of other repeats [2/21]

Time for a thread on our Christmas preprint “Origin and evolution of acrocentric chromosomes in human and great apes”. I had so much fun with this project and paper. It will be hard to summarize in a thread, but I’ll try www.biorxiv.org/content/10.6... [1/21]

It has been two weeks since the unexpected death of Peer Bork, and all of us in his research group are deeply missing him. His scientific vision brought us together as a team, and we are immensely grateful for the time we spent together. 🧵

Tandem repeats appear as rectangles in self-identity heatmaps. AniAnn’s literally “finds the rectangles” using edge detection and classifies them against a database of known repeat classes. Uses modimizers and matrix banding for speed. Try it out on your favorite T2T genome! Feedback appreciated!

New tool from @alexsweeten.bsky.social to find and classify all your satellites: "AniAnn's: alignment-free annotation of tandem repeat arrays using fast average nucleotide identity estimates"
📄 www.biorxiv.org/content/10.6...
📦 github.com/marbl/anianns

Congrats Rajiv!

Common variation in meiosis genes shapes human recombination and aneuploidy - Nature Analysis of data from pre-implantation genetic testing sheds light on the genetic basis of meiotic-origin aneuploidy, the leading cause of human pregnancy loss, identifying common genetic variants ass...

Pregnancy loss is common in humans, and chromosomal abnormalities are the leading cause. Using genetic data from ~140,000 IVF embryos, we show that maternal variation in meiosis genes influences recombination and aneuploidy risk.

First authors: @saracarioscia.bsky.social & @aabiddanda.github.io

Recently learned that I will be promoted to FULL PROFESSOR(!) this coming summer. So happy and thankful for those that have supported me along the way, including collaborators, mentors, colleagues, friends, family, trainees, and letter writers. #bighugs #youdabest #firstgen

Wonderful! Big congrats Megan!! 🎉

Clinical long-read genome sequencing for rare disease diagnostics Background Diagnostic evaluation of rare genetic disorders continues to rely on multiple test modalities, despite the increasing use of short-read exome or genome sequencing as first-tier tests. Long-...

1,000 PacBio genomes in a prospectively designed clinical utility study.
This was the biggest and most important study that made us go live in diagnostics.

Long-read genomes as a genetic first tier test across many rare diseases!
www.medrxiv.org/content/10.6...