I was reading Karlsson et al. (2014) and I came into this:

A selected variant that increases rapidly in frequency in the past ~250,000 years can be detected as an unusual reduction in genetic diversity.

I realised that I do not know how to infer a specific allele frequency over time within a given species.

I tried to googled some keyword but was flooded by other concepts. Could you please direct me to some appropriate documentation/kewords?

  • $\begingroup$ Welcome to Biology.SE. By tracing over time, I suppose you mean observing the signature of an allele sweeping to high frequency, are you? $\endgroup$ – Remi.b Apr 6 '16 at 15:33
  • $\begingroup$ I edited your post to include the link and fix the grammatical mistake (among vs within). You might want to add where the sentence comes from exactly (which page, which paragraph). $\endgroup$ – Remi.b Apr 7 '16 at 15:55

There's two parts to your post that I want to address, the first is the quote (because I want to make sure you understand it well), and the second is about general inference methods for estimating the genetic composition of ancestral populations.

The Quote: Selective Sweeps

A selected variant that increases rapidly in frequency in the past ~250,000 years can be detected as an unusual reduction in genetic diversity.

When an allele is selected for it will spread relatively quickly in the population, relative to the spread of neutral alleles for example. If an allele becomes fixed in the population the diversity in that gene is zero; there is no standing genetic variation in the gene. Selection will often reduce genetic variation but see this post too.

However, selection doesn't just reduce genetic diversity at the selected locus, but at loci near to the gene, those that are linked. The loss of genetic diversity at linked loci occurs by a process called a selective sweep. This is defined (somewhat poorly) in the web version of your linked paper:

Selective sweeps; Reductions in genetic variation caused by positive selection at particular loci.

Basically, a selective sweep occurs when strong selection causes one allele, and the loci it is highly linked to, to spread through a population. Genetic diversity will be lost from the linked loci at a rate determined by the strength of selection and the degree of linkage (where tighter linkage and stronger selection increase the rate of loss). This paper (see section 7 for selective sweeps) provides a good discussion of the factors affecting genetic variation in natural populations, and draws on the example of the Y chromosome:

One or more selective sweeps will have left the Y chromosome with little or no variability

Inference of ancestral populations

You could sample DNA of the population at the time you are interested in. However, doing so is very tricky. DNA degrades over time therefore it is important to have an understanding of how DNA degrades over time if you want to infer about the population. (I saw a talk a while back by a researcher, can't remember the name, taking samples from graves. I don't know how correctly I remember this, but much of the DNA they collect is bacteria. Just a tiny fraction of the DNA they got from sampling human bones found in graves that were just a few hundred years old was actually human. Another issue of studying old DNA). It's often difficult to find sources of DNA samples which a) of high enough quality and b) with enough individuals to allow good inference of the ancestral population; a small sample will be prone to sampling bias.*

There is another approach, and its commonly used now. If you are interested in finding more you should be searching for coalescent theory and methods. This infers back, based on current (or relatively more recent) genetic composition of populations and using population genetic theory. It's not really an used as an attempt to estimate the specific allele frequency, rather as an attempt to infer population size, migration rates, and recombination rates. It infers when was the most recent common ancestor (MRCA). This paper reviews coalescent methods for phylogenetic trees and this is an introduction lecture on coalescence. Coalescent theory has many considerations that need to be made; Are some mutations more common than others (see Molecular Clock)? How does selection affect genetic variation (e.g. selective sweeps)? Does linkage vary across the genome? Do rates of mutation, drift, and selection vary across the genome? Are different parts of the genome differently affected by migration?

Both approaches raise serious considerations which are at the forefront of evolutionary genetics right now. Research groups all over the world are developing lab methods, statistical methods, and mathematical models in an attempt to make inference more accurate. Right now the only way, in my opinion, to infer the frequency of specific alleles in ancestral populations is to use ancient DNA methods; coalescent can be used to infer population genetic parameters, but regarding specific alleles it just has so many factors to consider which (right now, but certainly less so in the future) we just don't have a thorough understanding of. In other words, the assumptions that need to be made for coalescence to be able to estimate specific ancestral allele frequencies are rarely going to be satisfied. However, as long as this is properly discussed there is no problem with the method being used, and I am certain that the future is bright for such methods.

*On sampling bias: Imagine you want to work out the frequency of the number two on a six-sided die (we know the true frequency is 0.167). You roll the die four times and the die shows the side with two dots once. You population frequency estimate is 0.25. Your friend rolls the same die 4000 times. They see the two dots 652 times, which is 0.163, much more representative of the true population frequency. The moral of the story, small samples can give misleading estimates of the truth.

  • $\begingroup$ Your answer has been very useful as I did not understand the selective sweeps at first, where the linkage explanation makes it clear. The first aim was to understand how to read the history of a gene frequency and @Resonating explained it well. $\endgroup$ – zakrapovic Apr 7 '16 at 14:32
  • $\begingroup$ I was just updating my answer to cover more of the approaches to inference @zakrapovic $\endgroup$ – rg255 Apr 7 '16 at 14:34

There are really two ways to infer past genetics.

  1. Sample the past.

Only really works if you have well-preserved uncontaminated archaeological samples, but works surprisingly well, considering. The accuracy and completeness goes down fairly quickly as you go back in time but thousands of years to hundreds of thousands of years is roughly possible. You won't have many samples so it's hard to say anything about population genetics. Don't do this. It doesn't work very well and it's very hard.

  1. Molecular clocks.

Same-sense mutations that affect nothing accumulate in genes over time as they're passed down. Genes that have a distant common ancestor are more different than genes that are just a generation or two apart. This is essentially how phylogenetics works as a whole, but you can use age differences between nearby genes to detect selection in this way. If gene A is nearly identical in every individual in a population, but gene B has thousands of pretty distinct variations, it's clear gene A does something important and has been powerfully selected for. Don't just count the number of kinds of alleles for gene A, calculate the average relatedness between all the alleles you find. If the relatedness for gene A is much lower than for other genes, gene A is being selected on. This is what the text means by 'reduction in genetic diversity', bringing down the average relatedness.

You can't work out allele frequencies at arbitrary times in the past without a time machine(even ancient sampling, you can't really be sure you're getting an accurate sample of the historical population), but phylogenetics can hint at what happened by detecting the signatures of evolution.

  • $\begingroup$ I did not know that we could sample the past and this is awesome. Then same-sens mutation explanation is clear. Many thanks $\endgroup$ – zakrapovic Apr 6 '16 at 20:26
  • $\begingroup$ I would guess, the article the OP is referring talks about genetic signature of selection (such as a selective sweep). Shouldn't this be a third big category? It is also unclear to me what inference on change in allele frequency through time you would like to do by comparing number of fixed difference in a single population. $\endgroup$ – Remi.b Apr 6 '16 at 20:30
  • $\begingroup$ Your guess is right $\endgroup$ – zakrapovic Apr 7 '16 at 8:16
  • $\begingroup$ @Remi.b Sorry, I think this needs an edit to be a little clearer. Measuring the number of fixed differences in a population isn't particularly robust, especially if the selection happened in the past. Something like 'mean relatedness' between many sampled alleles is much better and also lets you detect selection in subpopulations by looking at the distribution of scores. $\endgroup$ – Resonating Apr 7 '16 at 13:33

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