john hawks weblog

paleoanthropology, genetics and evolution

gene expression

  • Micro-RNA 941

    Sun, 2012-11-25 19:39 -- John Hawks

    John Timmer covers the story of miR-941, a micro-RNA that may influence the expression of genes in human brains, and which appears to have taken on a novel role in our lineage compared to other primates:

    Looking at the region in the human genome that contains miR-941 showed it's an area with a series of repeats of the same sequence, arranged in tandem. Chimps and macaques have similar sequences, but the duplications aren't arranged in a way that allows the production of a hairpin structure. Somewhere after we split off from chimps 6 million years ago, a rearrangement in the area (an event that's common in areas with duplicated sequences) created the human form of miR-941. It was already in place a million years ago, when the Denisovan population branched off.

    But the rearrangements didn't end there, as there have been a series of duplications that created as many as 11 extra copies of miR-941 (the numbers vary in different populations, but average is about six or seven copies in most). The extra copies should help ensure it's expressed at higher levels than it would be otherwise.

    The research was carried out by Hai Yang Hu and colleagues [1] in an open access paper ("Evolution of the human-specific microRNA miR-941". It deserves a bit more attention than I can give it at the moment, as it is one of a series of recent papers demonstrating human-specific duplications that affect gene expression. It is one of the first cases in which RNA structure and function have been investigated in an ancient genome. The number of copies of miR-941 varies substantially both within and among human populations.

    This passage from the paper is provocative:

    Humans display both increased longevity and increased occurrence of certain forms of cancer compared with both chimpanzees and macaques39. It is, therefore, appealing to speculate that emergence of miR-941 enhanced the maintenance of adult stem cell populations, thus supporting longer human lifespan, but rendering human cells more prone to malignant transformation. The role of miR-941 in the regulation of insulin signaling adds support to this notion. The insulin-signaling pathway was consistently implicated in lifespan regulation in many species, including humans. Notably, experimentally verified targets of miR-941 within this pathway include genes directly shown to be involved in lifespan extension in model organisms: IRS1, PPARGC1A and FOXO140 (ref. 40). Furthermore, FOXO1 was linked to extended human longevity.

    Still, I am skeptical of the idea that this molecule had a strong effect on the human phenotype. The greater the network of genes influenced by this micro-RNA, the less likely a massive up-regulation or down-regulation will have a simple phenotypic effect. Most genes that were duplicated or deleted during our evolutionary history probably were free to change because of a lack of fitness effect. Maybe this micro-RNA is an exception -- with a new effect on the human lineage, and extensive variation in copy number within humans. But it seems more likely to me that the variation in miR-941 dosage leads to a minor phenotypic effect across the network of affected genes, not a major directional effect.

    References

    1. Hu H, He L, Fominykh K, Yan Z, Guo S, Zhang X, Taylor MS, Tang L, Li J, Liu J, et al. Evolution of the human-specific microRNA miR-941. Nat Commun. 2012;3:1145.
    Tags: 
    brain
    brain function
    gene regulation
    gene expression
    micro-RNA

  • Making Big Data work in genetics

    Tue, 2012-05-15 15:33 -- John Hawks

    Laura Clarke and colleagues report on the data access and management practices of the 1000 Genomes Project [1].

    The larger data volumes and shorter read lengths of high-throughput sequencing technologies created substantial new requirements for bioinformatics, analysis and data-distribution methods. The initial plan for the 1000 Genomes Project was to collect 2× whole genome coverage for 1,000 individuals, representing ~6 giga–base pairs of sequence per individual and ~6 tera–base pairs (Tbp) of sequence in total. Increasing sequencing capacity led to repeated revisions of these plans to the current project scale of collecting low-coverage, ~4× whole-genome and ~20× whole-exome sequence for ~2,500 individuals plus high-coverage, ~40× whole-genome sequence for 500 individuals in total (~25-fold increase in sequence generation over original estimates). In fact, the 1000 Genomes Pilot Project collected 5 Tbp of sequence data, resulting in 38,000 files and over 12 terabytes of data being available to the community. In March 2012 the still-growing project resources include more than 260 terabytes of data in more than 250,000 publicly accessible files.

    The paper acknowledges that this large-scale genetic sequencing project nevertheless generates far less data than physics and astronomy projects. The Large Synoptic Survey Telescope, for example, will generate 20 terabytes each night of operation, while the Large Hadron Collider will generate roughly 15 petabytes per year. The 1000 Genomes Project data to date add up to around two weeks of LSST operation. Still, it's not hard to see how high-coverage sequencing will start to catch up in data storage and transfer requirements.

    We are now in a golden age of data centralization. But five years from now, we may return to a second era of disposable data, as gene expression and whole-genome resequencing studies will generate far more data than any central repository can store. We will need curation practices to identify and preserve data that have value beyond the project for which they were collected.

    The beautiful thing about this is that when data are abundant, they don't all have to work together. There is a real role for a new generation of curators to facilitate the mashups of the future.

    References

    1. Clarke L, Zheng-Bradley X, Smith R, Kulesha E, Xiao C, Toneva I, Vaughan B, Preuss D, Leinonen R, Shumway M, et al. The 1000 Genomes Project: data management and community access. Nature methods. 2012;9(5):459-462.
    Tags: 
    data access
    archiving
    curation
    genetics
    gene expression

  • Chimpanzee and human FOXP2 compared

    Wed, 2009-11-11 14:18 -- John Hawks

    A new paper in Nature (Konopka et al. 2009) reports on microarray expression comparisons of human and chimpanzee-specific versions of FOXP2. The change of two amino acids in the human version has some pretty large consequences for the expression of other genes.

    An accompanying essay by Martin Dominguez and Pasko Radic (2009) sums up the study in a paragraph:

    To further understand what FOXP2 does on a molecular level, two articles have revealed some of its probable targets, but neither study compared the regulatory effects of human and ancestral FOXP2. This is precisely what Konopka and colleagues have done, using whole-genome arrays to detect differences in gene expression in human neuronal cell lines expressing either human FOXP2 (FOXP2human) or the ancestral protein, FOXP2chimp. The authors find that a substantial number of FOXP2 target genes are differentially regulated by FOXP2human and FOXP2chimp. Many of these genes met the criteria for positive selection during human evolution (although the authors had no way of assessing their statistical significance). This places their findings in harmony with previous results that show FOXP2-related genes as evolutionary arbiters. Because the authors examine human-specific gene regulation by FOXP2, their work may provide our first window on the co-evolution of regulatory networks that are important for human-specific features such as language, which probably require a number of genetic changes working in concert.

    The "FOXP2" is not italicized here, because the passage refers to the protein product. I point that out to remind everybody that many important insights about gene function can only come from biochemical analysis of the resulting gene products. Most of us in paleoanthropology, even in the broadest sense encompassing genetics, don't

    What I really like about the result is that it shows FOXP2 is not some "magic gene" that suddenly triggered a cognitive revolution. It's a transcription factor that affects cell proliferation, with effects that cascade in many tissues. And it's highly conserved -- which means it's not like you could just switch it to a different form and expect everything to go right. The kind of genetic comparison that I can do shows the possibility of coevolution:

    Previously, we identified ChIP-chip targets of FOXP2 that themselves were also under positive selection6. We hypothesized that networks of genes important for language circuitry had been positively selected through selective pressure on human brain evolution. Thus, we also examined whether any differential FOXP2 targets were themselves under positive selection. Five genes (AMT, C6orf48, MAGEA10, PHACTR2 and SH3PXD2B) met the standard criteria of Ka/Ks > 1.0 for positive selection on the human lineage (where Ka indicates the rate of non-synonymous substitutions and Ks indicates the rate of synonymous substitutions; Supplementary Table 9). These data, along with the haCNS and expression data mentioned above, suggest that a subset of differential FOXP2 targets may have co-evolved to regulate pathways involved in higher cognitive functions.

    It seems to me that a cascade of genetic changes may have laid the groundwork for this regulatory shift, and that human populations may still be catching up to that shift today. Changes in these widely-interacting "hub" proteins have to be net good (or at least neutral) or they wouldn't have happened. But that doesn't mean that all their consequences are good -- they drag along a lot of bad effects with the good ones. So such changes may be followed by a series of genetic aftershocks -- changes in the "spoke" genes with functions compromised by the developmental/regulatory shift. Those changes might still be ongoing.

    Nor is FOXP2 the only candidate for such a system of genetic changes. The "haCNS" observation was this:

    A significant number of the differentially expressed genes [considering human- and chimp-FOXP2] are also associated with human-specific accelerated highly conserved non-coding sequences (haCNS), but not with chimpanzee highly conserved non-coding sequences....

    More on FOXP2:

    "How the FOXP2 transgenic mice squeak"

    "FOXP2 is really recent, it really did introgress (if it's not contamination)"

    "The amazing talking Neandertals"

    "FOXP2 knockout mice"

    References:

    Dominguez MH, Rakic P. 2009. Language evolution: The importance of being human. Nature 462:169-170. doi:10.1038/462169a

    Konopka G, Bomar JM, Winden K, Coppola G, Jonsson ZO, Gao F, Peng S, Preuss TM, Wohlschlegel JA, Geschwind DH. 2009. Human-specific transcriptional regulation of CNS development genes by FOXP2. Nature 462:213-217.

    Tags: 
    language evolution
    chimpanzees
    gene expression
    brain
    evo-devo
    Synopsis: 
    Konopke et al. (2002) report on expression profiles of human and chimpanzee FoxP2

  • If an olfactory receptor is expressed in your kidneys, what do they smell?

    Wed, 2009-01-28 00:54 -- John Hawks

    A reminder of the complexity of gene networks and their regulation:

    Functional expression of the olfactory signaling system in the kidney

    Jennifer L. Pluznick et al.

    Olfactory-like chemosensory signaling occurs outside of the olfactory epithelium. We find that major components of olfaction, including olfactory receptors (ORs), olfactory-related adenylate cyclase (AC3) and the olfactory G protein (Golf), are expressed in the kidney. AC3 and Golf colocalize in renal tubules and in macula densa (MD) cells which modulate glomerular filtration rate (GFR). GFR is significantly reduced in AC3−/− mice, suggesting that AC3 participates in GFR regulation. Although tubuloglomerular feedback is normal in these animals, they exhibit significantly reduced plasma renin levels despite up-regulation of COX-2 expression and nNOS activity in the MD. Furthermore, at least one member of the renal repertoire of ORs is expressed in a MD cell line. Thus, key components of olfaction are expressed in the renal distal nephron and may play a sensory role in the MD to modulate both renin secretion and GFR.

    On one level it makes perfect sense: you've got a highly specific molecule-sensing apparatus in one part of the body, and another part needs to detect some molecules and send signals about them. Evolution might well reuse parts of one system in the service of the other.

    On another level, it shows the difficulty of testing hypotheses about the evolution of single genes. The olfactory receptor genes have been repeated targets of selection in human (and primate) evolution. There has been a differential loss of functional OR genes in some primate lineages, including ours. A natural hypothesis is that we don't need to smell things that other mammals still need to smell, because primates are more vision-centric in their foraging and mating behavior.

    But then, what about the kidneys? Or other possible functions of OR genes in the body? Do they dampen the signal of selection? Enhance it? Are they independent of it? Are their kidney-specific regulatory elements for these genes? Or are there functional variants in olfaction that have functional side effects elsewhere?

    And what does any of this have to do with asparagus pee?

    Complicated.

    Tags: 
    pleiotropy
    gene expression
    olfaction
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Neandertals

For years, I've worked on their bones. Now I'm working on their genes. Read more about the science studying these ancient people.

Denisova

From a finger bone of an ancient human came the record of a completely unexpected population. My lab is working on the science of the Denisova genome.

Acceleration

The advent of agriculture caused natural selection to speed up greatly in humans. We're uncovering some of the ways that populations have rapidly changed during the last 10,000 years.

Malapa

Just outside Johannesburg, the Malapa site is producing some of the most exciting finds in human evolution. This site is the headquarters of the Malapa Soft Tissue Project.