Sociality, Hierarchy, Health Comparative Biodemography: A Collection of Papers (2014) / Chapter Skim
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5 Genomic and Evolutionary Challenges for Biodemography--Kenneth M. Weiss
5 Genomic and Evolutionary Challenges for Biodemography--Kenneth M. Weiss
Pages 95-120
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From page 95... ...
This applies particularly to behavior traits that are hard to define and affected by experience. Improved ability to relate genetic effects to age patterns, and hence life history, reflects causal mechanisms and could be a fruitful area of research.
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From page 96... ...
These biodemographic phenomena generate life history-based nested descent trees, but DNA sequence samples from the population may not be a very reliable indicator of the integrated genome of each individual. The effect of somatic mutation, overlaid on inherited genotype, results in a net FIGURE 5-1 Symmetry between evolutionary and somatic genomic variation trees.
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From page 97... ...
Instead of explicit theoretical modeling, genomic causal inference typically has rested on inductive, exhaustively reductionist, retrospective data fitting, rather than rigorous prediction. The approaches rest essentially on generic statistical association and regression models, which are mechanism-free approaches that, in the presence of the kinds of complex causation I will try to outline, can lead to conclusions so indirect as to provide weak predictive power and hamper undertanding of causal mechanisms at the genetic or evolutionary level.
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From page 98... ...
Many short DNA sequences near a gene are bound by proteins (themselves coded for by genes elsewhere in the genome, with their own comparable structure)
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From page 99... ...
have receptors for specific signals; next, local cell differentiation activated over time by the receipt Figure 5-2B of appropriate combinations of signals and receptors, coded from various genes in various cellular sources elsewhere. The lower panel shows that this is a multiple step, hierarchical phenomenon without a beginning or end: a trait is studied by measuring some chosen set of cells at some time (or by ignoring all of this and assumng i causation can be inferred from the inherited genome alone)
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From page 100... ...
. Humans are the collective product of the population processes of evolution, and if one holds the strong adaptationist view that almost every thing that is functional has been made so by natural selection, then an obvious criterion for function is DNA sequence conservation: Functional sequence should not vary much compared to parts of DNA with no or little apparent function.
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From page 101... ...
and transcribed RNAs of various directly functional types other than protein-coding, research has only gone slightly beyond this classical linear-causation view. That in part explains why the basic methodologies for finding genomic causality have not fundamentally changed.
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From page 102... ...
But it has been shown that context- pecific s "epigenetic" chemical changes do modify DNA molecules in ways that affects gene usage, without changing their nucleotide sequence. Epigenetic changes can be inherited and thus mimic Mendelian familial correlations (Flanagan et al., 2006; Petronis, 2010)
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From page 103... ...
What? The vertical transmission of somatic mutations generates a hierarchical descent tree of variation among the tissues as part of each person's life history.
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From page 104... ...
constitutive sequences, sometimes assessing function by comparison with an arbitrary reference. This is a strange definition of "normal" since the donors of "the" sequence will eventually incur a variety of age-related disorders that may be affected by their particular genotype.
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From page 105... ...
Most sites identified by genome-wide mapping methods, such as comparing variation in cases with controls, contribute only trivially small individual effects, such that sample structure and arbitrary significance criteria are more important than biology in whether they are identified. A long-standing argument, or I would say defense of (or excuse for)
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From page 106... ...
For the same reason cross-species comparative analysis presents fundamental challenges. The challenge is greater if genomic action is interactive with lifestyles and yields gradual effects on age-related life history functions.
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From page 107... ...
Without adequate formal theory for what to expect to find, this means finding strong effects will perforce ignore smaller ones that may be present. Significance cutoffs are important and have been explicitly used to avoid having to follow up a sea of false positives, but they force the apparent fact that many or even the bulk of causal effects are too small to detect with chosen cutoff criteria.
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From page 108... ...
What is now known about genomes and causal complexity stretches the ability of current explanations and methods to account adequately for is seen, with implications for both experimental and comparative research. Indeed, what is known affects basic epistemological criteria.
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From page 109... ...
This relates to sequence conservation, which I mentioned earlier is a commonly invoked criterion for biological function. If polygenic contributors have only weak individual effects, these effects may be ephemeral even in the presence of natural selection.
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From page 110... ...
Also as noted earlier, over time evolution generates genomic divergence both within and between populations. For this reason, meta-analysis relies on detecting older variants still found in populations descendant from a common founding population.
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From page 111... ...
There are tens of different paths to vision and many other traits for which there are data. Polygenic control shows that there are countless ways to the same height, body mass index, psychopathology, or blood pressure.
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From page 112... ...
. Rather than a Darwinism-Mendelian duality in which individual genetic variants are the causally deterministic units of life, fixed by an equally d eterministic force like Darwinian natural selection, life has evolved to be a multidimensional web, with at least a generic statistical spectral structure of effects.
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From page 113... ...
At least, given the nature of genomic causal complexity, one should be clear what serious biodemographic information would justify the time and cost of attempting to reduce to genomic terms. Isolating Age Effects and Developing Useful Theory Where it seems appropriate, even for basic knowledge, there is still much to be learned about the basic mechanisms by which genomic variation affects age-specific risk or outcomes.
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From page 114... ...
Still, mapping studies have rarely made serious attempts to fit hazard functions to genomic effects, site-by-site or in aggregate. One might adjust current regression approaches to do that.
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From page 115... ...
will be as hard to detect as causal factors in contemporary mapping studies. Slow evolution generates, or at least tolerates, complex variation.
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From page 116... ...
Whatever the answer, this is a time of discovery by enumerative induction, enamored with mass data collection for various venal, bureaucratic, as well as scientifically legitimate reasons, but which has, to date, yielded only limited ability to generalize or extrapolate. In my view, there should be major investment in innovative attempts to d evelop better theory for well-posed questions, rather than mega-projects of standard types, essentially to refine statistical evidence or association that may not point very directly to genomically causal elements of importance.
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From page 117... ...
. Variations in DNA elucidate molecular networks that cause disease.
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From page 118... ...
. Intra- and interindividual epigenetic variation in human germ cells.
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From page 119... ...
. FTO genotype is associated with phenotypic variability of body mass index.
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