10,000 years of gene changes: increasing many health problems, 2 Vitamin D changes, – Aug 2022

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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.
 Download the PDF from VitaminDWiki

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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VitaminDWiki - Vitamin D Binding Protein category listing has 178 items and contains

Vitamin D Binding Protein (GC) gene can decrease the bio-available Vitamin D that can get to cells,

• GC is not the only such gene - there are 3 others, all invisible to standard Vitamin D tests
• The bio-available calculation does not notice the effect of GC, CYP27B1, CYP24A1, and VDR
• The actual D getting to the cells is a function of measured D and all 4 genes
• There is >2X increase in 8+ health problems if have poor VDBP (GC)
• It appears that VDBP only blocks oral vitamin D,
  • but NOT Vitamin D from sun, UV, topical or inhaled (tissue activated)
  • A clue: - Vitamin D from UV is 2X better for MS than oral Vitamin D

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List of Vitamin D Binding Protein health problems

Increased Risk	Health Problem
11 X	Preeclampsia
6.5X	T1D in SA Blacks
6 X	Food Allergy
5 X	PTSD
4 X, 5X	Kidney Cancer
4 X	Poor Response to Oral Vitamin D
3 X	Ear infection
2.8 X	MS
2.5 X	Severe Autism
2 X	Colorectal Cancer
2 X	Prostate Cancer -in those with dark skins
1.3 X	Infertility

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VitaminDWiki pages with DHCR7 in title (6 as of Sept 2022)

This list is automatically updated