Lamprey genome sequenced

This blog post is reposted with permission from BEACON faculty member C. Titus Brown’s blog, Living in an Ivory Basement.

LampreyThe lamprey is a jawless vertebrate that diverged from the jawed vertebrate lineage around 550 mya. Lampreys, together with hagfish, represent the last extant vestiges of the evolutionary lineage bounded by invertebrate chordates — organisms without vertebrate features — and jawed vertebrates, which include fish, frogs, and mammals.

The genome was a gigantic pain in the butt. We (and by “we” I mean Jeramiah Smith, the first author) could only assemble 800 Mbp, a maximum of 2/3 of the estimated complete genome (which is in the range of 1.2-1.6 Gbp, depending on which estimates you believe). This is partly because the genome has a bunch of really annoying GC-rich repeats that confounded much of our BAC sequencing and hence much of our scaffolding.

The other reason for the incompleteness of the genome is much less common and more problematic: we constructed our sequencing libraries from liver, which, in the lamprey means that we’re missing 20% or more of the genome. This is because the lamprey genome undergoes lineage-specific loss of genomic DNA. (At this point you should say “WHAT? WHY!?” and/or lament the cost of sequencing and analyzing a subset of the germ line genome :).

Remember, genomics is out to get you.

What’s the single most interesting take-home observation?

The main section to read, I think, is “Duplication structure of the genome.” Here, we (again, mostly Jeramiah, with a lot of input from others) argue that synteny analysis shows

“the most recent (two-round) whole-genome duplication event likely occurred in the common ancestral lineage of lampreys and gnathostomes.”

Other things discussed are

we (i) provide genome-wide evidence for two whole-genome duplication events in the common ancestral lineage of lampreys and gnathostomes, (ii) identify new genes that evolved within this ancestral lineage, (iii) link vertebrate neural signaling features to the advent of new genes, (iv) uncover parallels in immune receptor evolution and (v) provide evidence that a key regulatory element in limb development evolved within the gnathostome lineage.

So, overall, pretty cool.

My main involvement in the nitty gritty of this paper was a sadly failed attempt to use protein domain alignment to determine the duplication structure of the genome. Because the initial assembly we had was not very good (it was considerably worse than the one that finally got published!), I tried to develop a novel approach using PFAM models to drive gene/domain alignment, followed by automatic tree examination. This approach unambiguously indicated that there had been no 2R. However, a few months later, after I did some QC and ran some models, it turned out that the approach was extraordinarily sensitive to gene loss. This occasioned a very embarrassing e-mail to the lamprey genome list, sigh.

(Genomics really is out to get you.)

The syntenic 2R analysis on a new Jeramiah-generated assembly turned out to be much better and argued for the pre-divergence 2R scenario.

Are you still working on lamprey?

The lamprey genome is one of two projects that launched my research into assembly; digital normalization was, in large part, driven by the desire to assemble approximately 5 billion mRNAseq reads produced by Weiming Li’s lab. We were driven to do this by the poor quality of the initial lamprey genome, and the newer revelation that large portions of the genome are simply missing. (In general, it seems like the genomics research community is starting to realize that mRNAseq is a complementary approach to genome assembly, which is often quite hard.

Our paper on assembling massive mRNAseq is still in the process of being written. Preliminary results from that work indicate that we do see about 20-30% of transcribed & conserved genes missing from the lamprey genome, but we’re still nailing down the numbers — large transcriptome assemblies turn out to be really messy!

You can see the paper here  and the Michigan State University press release here. For more information about Titus’ work, you can contact him at ctb at msu dot edu.

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