What is the TCC/TTC shift?

The TCC/TTC shift was a genome-wide mutation pattern discovered by Kelley Harris and Jonathan Pritchard in 2017. By comparing mutation rates of key haplotypes between modern humans and their ancestral states (here modelled using chimpanzee homologs), accelerated rates of TCC to TTC mutations were found in key populations. 

What does this effectively mean? 

Human DNA contains four main bases: adenine, thymine, cytosine and guanine, usually abbreviated as A, T, C and G respectively. These are essentially chemicals that run on the inside of the DNA and the sequences of these determine which amino acids are combined to form a protein. Proteins are molecules in the body that are involved in many different functions -- hormones, signals, enzymes, transporters and structures. (The process through which amino acid chains become functional proteins is a little more complicated and beyond the scope of this blog post.) Over generations, random changes in the sequence of bases, called mutations, take place. Sometimes, the rate of change is affected by external factors. 

However, Harris and Pritchard identified something unusual. In the ancestors of modern Europeans, wherever the base sequence TCC occurred, regardless of their position in a DNA strand, this tended to mutate to TTC. While the mutation rates of other sequences were fairly constant, the mutation of TCC to TTC happened more quickly than in other sequence mutations. 

Which populations were affected? 

The strongest signals were found in Europeans, followed by South Asians. Populations in Africa and East Asia were unaffected. Central Asians would likely form an intermediate pattern between Europeans and South Asians, but there were no data for these people in the 1000 Genome Project (used in Harris and Pritchard's study). 

Above image: TCC/TTC mutation rates in different continental groups (Harris and Pritchard 2017). 

This shift would have occurred in a population group ancestral to modern Europeans. This group would have also contributed to the genetic composition of modern South Asians, although to a lesser extent than of Europeans. 

When did this shift occur? 

Speidel (2021) positions this shift between 15,000 and 30,000 years before the present (BP). The signal is shown to be exhibited at a high amplitude by 15,000 BP but there is no evidence for this prior to 30,000 BP. 

What are the potential implications of this finding? 

As the mutation shift occurred in the ancestors of modern population groups, we can use this to evaluate sex bias in ancestral migrations. Analysis in ancient samples shows the strongest signals around the Caucasus and Eastern Anatolia with some signals around the Steppe due to background admixture (Speidel 2021). Signals are strongest around the source population and diffuse with subsequent admixture; hence, we can establish that this is where the mutation shift originated. By comparing the amplitude and mutation rates of this signal between the X chromosomes and autosomes, we can establish what proportion of the descendants of this ancestral population migrating to Europe and Asia were male and female. If we assume that mutation rates between chromosomes are equal (which is reasonable as this shift occurred throughout the genome) then the mutation rates and shifts should be 3/4 as strong in the X chromosomes of descendent populations in comparison to the autosomes. This is because, for every four autosomes in a population of equal numbers of men and women, there are three X chromosomes (and one Y chromosome). By analysing how this signal ratio deviates from 1:3/4, we can quantify sex-biased ancestral input from Western Asia in modern populations. 

What is still unknown? 

The finding is rather an enigma. It has been suggested that this shift results from short generation times in ancestral populations (Macia et al., 2021), but this fails to explain why this only affected a specified sequence and not others. It is reasonable to suggest that a mutation in the machinery affecting the DNA repair of the TCC sequence spread in an ancestral population but was later lost in descendent populations. How this mutation could fix within a population and then disappear many centuries or millennia later is not clear. 

References: 

• Harris and Pritchard 2017, Rapid evolution of the human mutation spectrum, https://doi.org/10.7554/eLife.24284 
• Speidel et al. 2021, Inferring Population Histories for Ancient Genomes Using Genome-Wide Genealogies, Molecular Biology and Evolution, https://doi.org/10.1093/molbev/msab174 
• Macia et al. 2021, Different historical generation intervals in human populations inferred from Neanderthal fragment lengths and mutation signatures, Nature, https://doi.org/10.1038/s41467-021-25524-4