10,000 years of gene changes: increasing many health problems, 2 Vitamin D changes,

1,000 ancient genomes uncover 10,000 years of natural selection in Europe

Preprint bioRxiv preprint doi: https://doi.org/10.1101/2022.08.24.505188;

Megan K. Le1, Olivia S. Smith2, Ali Akbari3,4,7, Arbel Harpak2,54, David Reich3,4,6,74 & Vagheesh M. Narasimhan2,84

1 Department of Computer Science, The University of Texas at Austin

2 Department of Integrative Biology, The University of Texas at Austin

3 Department of Genetics, Harvard Medical School

4 Department of Human Evolutionary Biology, Harvard University

5 Department of Population Health, Dell Medical School

6 Howard Hughes Medical Institute, Harvard Medical School

7 Broad Institute of MIT and Harvard

8 Department of Statistics and Data Science, The University of Texas at Austin

4 Co-corresponding authors

Ancient DNA has revolutionized our understanding of human population history. However, its potential

to examine how rapid cultural evolution to new lifestyles may have driven biological adaptation has not

been met, largely due to limited sample sizes. We assembled genome-wide data from 1,291 individuals

from Europe over 10,000 years, providing a dataset that is large enough to resolve the timing of selection

into the Neolithic, Bronze Age, and Historical periods. We identified 25 genetic loci with rapid changes

in frequency during these periods, a majority of which were previously undetected. Signals specific to the

Neolithic transition are associated with body weight, diet, and lipid metabolism-related phenotypes. They

also include immune phenotypes, most notably a locus that confers immunity to Salmonella infection at a

time when ancient Salmonella genomes have been shown to adapt to human hosts, thus providing a

possible example of human-pathogen co-evolution. In the Bronze Age, selection signals are enriched near

genes involved in pigmentation and immune-related traits, including at a key human protein interactor of

SARS-CoV-2. Only in the Historical period do the selection candidates we detect largely mirror

previously-reported signals, highlighting how the statistical power of previous studies was limited to the

last few millennia. The Historical period also has multiple signals associated with vitamin D binding,

providing evidence that lactase persistence may have been part of an oligogenic adaptation for efficient

calcium uptake and challenging the theory that its adaptive value lies only in facilitating caloric

supplementation during times of scarcity. Finally, we detect selection on complex traits in all three

periods, including selection favoring variants that reduce body weight in the Neolithic. In the Historical

period, we detect selection favoring variants that increase risk for cardiovascular disease plausibly

reflecting selection for a more active inflammatory response that would have been adaptive in the face of

increased infectious disease exposure. Our results provide an evolutionary rationale for the high

prevalence of these deadly diseases in modern societies today and highlight the unique power of ancient

DNA in elucidating biological change that accompanied the profound cultural transformations of recent

human history.

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Gene modifications over 10,000 years of European history Shows when various health problems started occuring after leaving hunter gatherer stage. etc Health problems were a side effect of gene modifications The 2 Vitamin D changes happened about 3,000 years ago

Change in DHCR7 and VitaminD Binding Protein

Clipped from PDF

Candidate selective signals most intense during the transition to the Historical Period

The variant with the strongest significant deviation from expectation is in the LCT gene, which is

responsible for conferring the ability to digest lactose in adulthood in Europeans. This is also consistently

the strongest signal of natural selection detected in scans in modern Europeans, and in line with findings

in previous publications65, this allele appears to have experienced its major change in frequency primarily

in the past few thousand years, and not during the Bronze Age when the allele was first introduced in

central and western Europe.

We found a selective signal in DHCR7 (the focal SNP that deviates most from expectation is in

an enhancer region several kb upstream of the gene), which governs availability of 7-dehydrocholesterol

for conversion to vitamin D3 by the action of sunlight on the skin. Milk is rich in 7-dehydrocholesterol,

suggesting that selection on this locus as well as LCT might have been related to the need for increased

production of vitamin D66. This locus has also been linked to several auto-immune diseases. We also

detect evidence for deviation in allele frequency from expectation in the missense variant rs653178 in the

gene SH2B3. This allele doubled in frequency from the Bronze Age to the Historical period and is a major

risk locus for Celiac disease. The allele we identify as a signal of selection has recently also been shown

to be fine-mapped in a GWAS for vitamin D binding67. Functional investigation of the effect of the

SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide revealed that carriers of the

SH2B3 allele showed stronger activation of the NOD2 recognition pathway. This suggests that SH2B3

also plays a role in protection against bacterial infection68.

Increased incidence of diseases to to gene changes

Very difficult to understand this chart, even after reading the PDF

Fig. 4: Signals of polygenic selection. Traits shown in red in a given epoch are ones for which we find evidence for post-admixture selection favoring trait-increasing alleles during that epoch. Traits shown in blue show evidence for trait-decreasing in that epoch. In gray are non-significant results. The within-sib GWAS results are only available for a small subset of traits that overlap with BBJ and have a greatly reduced number of SNPs that are genome-wide significant in the GWAS (SNP counts shown in brackets where available). These rows with unavailability of GWAS results for traits from within-sib GWAS are left blank.

Portion of insight

One important set of insights relates to the genomic impact of the major transition from hunting

and gathering to farming. A set of alleles that were targets of selection in this period have to do with

decreased body weight/size. Complementarily, the archeological record also shows an overall decrease in

body size during the Neolithic transition 95. One hypothesis is that a reduction in overall calorie intake, a

trait that would be genetically correlated with reduced body weight, was advantageous in the Neolithic

when famines and resource instability became more frequent96. Similarly, selection for more efficient

storage and use of glucose in tissues during periods of famine or pathogen outbreaks might also underlie

several of our selection signals associated with insulin secretion, regulating glucose in the blood stream.

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