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29.4: Natural Selection

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    41137
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    In the mid 1800s the concept of evolution was not an uncommon idea, but it wasn’t before Darwin and Wallace proposed natural selection as the mechanism that drives evolution in nature that the theory of evolution got widespread recognition. It took 70 years (1948) until J.B.S Haldanes Malaria Hypothesis found the first example for natural selection in humans. He showed a correlation between genetic mutations in red blood cells and the distribution of malaria prevalence and discovered that individuals who had a specific mutation that made them suffer from sickle cell anaemia also gave made them resistant to malaria.

    Lactose tolerance (lasting into adulthood) is another example of natural selection. Such explicit examples were hard to prove without genome sequences. With whole genome sequencing readily available, we can now search the genome for regions with the same patterns as these known examples to identify further regions undergoing natural selection.

    Genomics Signals of Natural Selection

    • Ka/Ks ratio of non-synonymous to synonymous changes per gene
    • Low diversity and many rare alleles over a region (ex Tajima’s D with regard to sickle-cell anemia)

    • High derived allele frequency (or low) over a region (ex Fay and Wu’s H)
    • Differentiation between populations faster than expected from drift (Measured with Fst)
    • Long haplotypes: evidence of selective sweep.
    • Exponential prevalence of a feature in sequential generations
    • Mutations that help a species prosper

    page485image38544528.png
    Figure 29.5: Approximate Time Table of Effects Sabeti et al. Science 2006

    American Association for the Advancement of Science. All rights reserved. This content is excluded

    from our Creative Commons license. For more information, see http://ocw.mit.edu/help/faq-fair-use/.

    Source: Sabeti, P.C., et al. "Positive Natural Selection in the Human Lineage." Science 312, no. 5780

    (2006): 1614-20.

    Examples of Negative (Purifying) Selection

    Across species we see negative selection of new mutations in conserved functional elements (exons, etc.).

    New alleles within one species tend to have lower allele frequencies if the allele is non-synonymous than synonymous. Lethal alleles have very low frequencies.

    Examples of Positive (Adaptive) Selection

    • Similar to negative selection in that positive selection more likely in functional elements or non-

      synonymous alleles.

    • Across species in a conserved element, a positively selected mutation might be the same over most mammals, but change in a specific species because a positvely selected mutation appeared after speci- ation or caused speciation.

    • Within a species positvely selected alleles likely differ in allele frequency (Fst) across populations. Examples include malaria resistance in African populations (29.6) and lactose persistence in European populations (29.7).

    • Polygenic selection within species can arise when a trait is selected for that depends on many genes. An example is human height where 139 SNPs are known to be related to height. Most are not population specific mutations but alleles across all humans that are seleced for in some populations more than others. (29.8)

      page486image38602368.png
      Figure 29.6: Localized positive selection for Malaria resistance within species Sabeti et al. Science 2006

    Statistical Tests

    • Long range correlations (iHs, Xp, EHH): If we tag genetic sequences in an individual based on their ancestry, we end up with a broken haplotype, where the number of breaks (color changes) is correlated with the number of recombinations and can tell us how long ago a particular ancestry was introduced.
    • SWEEP A program developed by Pardis Sabeti, Ben Fry and Patrick Varilly. SWEEP detects evidence of natural selection by analyzing haplotype structures in the genome using the long range

    page487image38721216.png
    American Association for the Advancement of Science. All rights reserved. This content is excluded

    from our Creative Commons license. For more information, see http://ocw.mit.edu/help/faq-fair-use/.

    Source: Sabeti, P.C., et al. "Positive Natural Selection in the Human Lineage." Science 312, no. 5780

    (2006): 1614-20.

    Figure 29.7: Localized positive selection for lactase persistence allele Sabeti et al. Science 2006

    page487image38729952.png
    Courtesy of Macmillan Publishers Limited. Used with permission.

    Source: Turchin, Michael C., et al. "Evidence of Widespread Selection on Standing Variation

    in Europe at Height-associated SNPs." Nature Genetics 44, no. 9 (2012): 1015-9.

    Figure 29.8: Mean allele frequency difference of height SNPs, matched SNPS, and genome-wide SNPS between Northern- and Southern-European populations
    Turchin et al., Nature Genetics (2012)

    haplotype test (LRH). It looks for high frequency alleles with long range linkage disequilibrium that hints to large scale proliferation of a haplotype that occurred at a rate greater than recombination could break it from its markers .

    High Frequency Derived Alleles Look for large spikes in the frequency of derived alleles in set positions.

    High Differentiation (Fst) Large spikes in differentiation at certain positions.

    Using these tests, we can find genomic regions under selective pressure. One problem is that a single SNP under positive selection will allow nearby SNPs to piggy-back and ride along. It is dicult to distinguish the SNP under selection from its neighbours with only one test. Under selection, all the tests are strongly

    page488image38525856.png
    Figure 29.9: Broken haplotype as a signal of natural selection

    correlated; however, in the absence of selection they are generally independent. Therefore, by employing a composite statistic built from all of these tests, it is possible to isolate the individual SNP under selection.

    Examples where a single SNP has been implicated in a trait:

    • Chr15 Skin pigmentation in Northern Europe

    • Chr2 Hair traits in Asia
    • Chr10 Unknown trait in Asia
    • Chr12 Unknown Trait in Africa


    29.4: Natural Selection is shared under a not declared license and was authored, remixed, and/or curated by LibreTexts.

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