Genome-wide studies, particularly from ancient samples, have substantially expanded our understanding
of human evolutionary history. However, ancient DNA (aDNA) research has remained
a challenging field, due to post-mortem DNA damage and contamination. While these are unavoidable,
technological and methodological improvements have made it possible to assess their
potential effect on the data and results. We have implemented and extensively tested a statistical
method for estimating contamination from high-throughput sequencing data based on haploid
chromosomes (Chapter 2). We found our method to produce reliable results even for datasets with
limited depth of coverage (0.5X) and high error rates. This feature is particularly well suited for
aDNA studies where it is unlikely to produce higher-coverage genomes. Moreover, we have developed
a tool that allows for ancestry assessment of low-coverage data using multidimensional
scaling (Appendix A). These and similar methods have been applied in a number of studies that
have contributed to generating a more detailed description of human dispersals across the globe.
It is now accepted that anatomically modern humans expanded out of Africa and colonized most
of the Old World by 30 kya. Subsequently, they crossed Beringia, the land bridge connecting
Northeast Asia and Alaska, after the Last Glacial Maximum. However, archaeology, anthropology,
linguistics and even genetics have not reached a consensus on key aspects such as the number of
migration waves, their origin and their time and routes of entrance. We sequenced the first highcoverage
human genome (USR1) from Terminal Pleistocene Alaska; the most likely entryway into
the New World (Chapter 3). The USR1 genome revealed a basal Native American population that
likely diverged in Beringia from Native Americans, which later differentiated beyond the glacial ice
sheets. Our findings support a single founding source population for all Native Americans. These
include human remains that have been hypothesized to be members of a separate migration from
the Old World, such as the Kennewick Man for which we confirmed his Native American origin
(Appendix B). Moreover, the USR1 genome allowed us to re-assess the source of two secondary
migrations that likely gave rise to Na-Dene-speaking and Inuit populations. We conclude that both
derive their Native American ancestry from a similar source; however, they carry ancestry from
two different Asian migrations. Finally, we explore a more recent, trans-Pacific contact between
Polynesians and Native Americans (Chapter 4). We analyzed genotype data from modern-day
Rapanui and found that they carry Native American ancestry, which derives from an admixture
event that antedates the presence of Europeans in the region. These findings provide new insights
into the initial peopling of the Americas as well as secondary contacts with an unprecedented
resolution, which could only be achieved by generating genome-wide data.