The uncertainty of population relationship and divergence time inferred by the multiple sequentially Markovian coalescent model

The human colonization and adaptation of Tibetan Plateau attract wide concerns in recent years. To date, the permanent human occupation of Tibetan Plateau is a topic of hot dispute in archaeology [1, 2]. Massive genetic studies have been conducted to address this issue by estimating the divergence time between highland Tibetans and lowland populations (e.g., Han; Table S1). The comprehensive analyses of mitochondrial DNA and Y chromosome markers revealed at least two distinct migratory waves into the Tibetan Plateau. The early Upper Paleolithic migration was dated ~30 kilo years ago (kya); in addition, the later Neolithic colonization was traced back to 10–7 kya [3, 4]. By analyzing data of exome and genome-wide single-nucleotide polymorphisms, Tibetan and Han populations were proposed to diverge 2750 [5] and 4725 years ago [6], respectively. The two recent studies based on whole-genome re-sequencing dated this divergence to 15–9 kya [7] and 58–44 kya [8], respectively. Thus, the time for divergence between Tibetan and other populations is still in chaos.

When did Tibetan split from other populations? We cannot give a clear answer to this question based on current analyses of genomic data. Indeed, our results can provide some caveats here. Because of the relative high computation load [9], MSMC is usually run based on two or four haplotypes [7, 8, 10]. Our results suggest that sample size plays substantial roles in MSMC analyses. How to interpret the differences in the inference of population relationship and divergence time based on eight and four haplotypes is still unclear. Using eight haplotypes, which contain more genetic information, could be a preferential choice. In addition, MSMC cross coalescence rates behave roughly linear under admixture [11]. The investigation of genetic admixture in individuals used in MSMC analysis may be required. Taken above, the uncertainty of population relationship as well as divergence time between Tibetan and other populations should be considered, especially in demographic inference.

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