Some Rare Variants are Recent and Some Old

That rare variants are, in general, recent does not contradict our results. On the contrary, that the majority of IBD segments extracted by HapFABIA is found in Africans can explain why three times as many variants with 0.5-5% minor allele frequency are found in Africans as in European or Asians in the 1000 Genomes Project (2). In particular, if rare variants are caused by a recent population growth, then the numbers found by the 1000 Genomes Project (2) are difficult to interpret. We want to discuss two reasons why rare variant may be old.

(I) Many rare variants are old, however, most rare variants may be recent, e.g. because of a recent growth in population. We did not consider private variants and have a bias toward less rare variants because, the more individuals share an IBD segment, the higher its significance, the more likely it is detected by HapFABIA. In our analysis, only 39% of the rare variants (not counting private variants) are in IBD segments. Therefore, the remaining majority of rare and private variants might be recent.

The vast majority of IBD segments is found in Africans. This would explain why Africans have more rare and low frequent variants than Europeans or Asians. The publication of the 1000 Genomes Project (2) reports:

``individuals from populations with substantial African ancestry (YRI, LWK and ASW) carry up to three times as many low-frequency variants (0.5-5% frequency) as those of European or East Asian origin,''

Table S14 in the supplementary information of the publication of the 1000 Genomes Project (2) provides the number of derived variants per individual in each population in its last rows (DAF denotes ``derived allele frequency'', i.e. the frequency of the mutation):

	African			European
	ASW	LWK	YRI	CEU	FIN	GBR	IBS	TSI
DAF $<$ 0.5%	116,216	152,267	122,978	30,034	32,918	31,944	36,129	33,425
DAF 0.5-5%	558,996	649,303	683,239	143,987	146,737	146,802	155,270	146,066
	Asian			admixed American
	CHB	CHS	JPT	CLM	MXL	PUR
DAF $<$ 0.5%	36,081	40,974	45,107	45,184	38,654	48,892
DAF 0.5-5%	119,668	118,137	120,115	189,257	163,737	214,430

  

Recent variants are supposed to be derived variants. The table shows about four times more variants with derived allele frequency of 0.5-5% in Africans than in other populations (if we ignore the admixed Americans that have African admixture). For derived allele frequency $<$ 0.5%, we observe 2.5 times more variants in Africans than in Europeans or Asians.

(II) Many rare variants are old, however, compared to common SNPs, they are recent, i.e. the temporal relations remain, but variants are dated further back. We state in the manuscript that many rare variants are old and from times before humans migrated out of Africa. However, many common SNPs are even older and stem from common ancestors of human and chimpanzee. This means that many rare variants are old, but compared to common SNPs they are recent.

That common SNPs are old is supported by findings of the Chimpanzee Consortium. In Hacia et al. (37) it was found that, of 397 human SNP sites, 214 were ancestral (shared with common ancestors of chimpanzee and human). Of the ancestral SNPs, 1/4 had the minor allele as ancestral allele. For the chimpanzee genome (38), it was found that

``Of $\sim$ 7.2 million SNPs mapped to the human genome in the current public database, we could assign the alleles as ancestral or derived in 80% of the cases according to which allele agrees with the chimpanzee genome sequence''

and that

``a significant proportion of derived alleles have high frequencies: 9.1% of derived alleles have frequency $\geq$ 80%.''

According to (38, Suppl. Fig. S9) about 25% of the derived alleles have frequency $\geq$ 50% in which case the minor allele is the ancestral allele.

That some SNPs are very old and that some haplotypes are shared between humans and chimpanzee was also found in Leffler et al. (39):

``We conducted a genome-wide scan for long-lived balancing selection by looking for combinations of SNPs shared between humans and chimpanzees. In addition to the major histocompatibility complex, we identified 125 regions in which the same haplotypes are segregating in the two species,''