One in three women in Europe inherited the receptor for progesterone from Neanderthals associated with increased fertility

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One in three women in Europe inherited the receptor for progesterone from Neanderthals – a gene variant associated with increased fertility, fewer bleedings during early pregnancy and fewer miscarriages.

This is according to a study published in Molecular Biology and Evolution by researchers at the Max Planck Institute for Evolutionary Anthropology in Germany and Karolinska Institutet in Sweden.

“The progesterone receptor is an example of how favourable genetic variants that were introduced into modern humans by mixing with Neandertals can have effects in people living today,” says Hugo Zeberg, researcher at the Department of Neuroscience at Karolinska Institutet and the Max Planck Institute for Evolutionary Anthropology, who performed the study with colleagues Janet Kelso and Svante Pääbo.

Progesterone is a hormone, which plays an important role in the menstrual cycle and in pregnancy. Analyses of biobank data from more than 450,000 participants – among them 244,000 women – show that almost one in three women in Europe have inherited the progesterone receptor from Neanderthals.

Twenty-nine percent carry one copy of the Neanderthal receptor and three percent have two copies.

Favourable effect on fertility

“The proportion of women who inherited this gene is about ten times greater than for most Neandertal gene variants,” says Hugo Zeberg. “These findings suggest that the Neanderthal variant of the receptor has a favourable effect on fertility.”

The study shows that women who carry the Neandertal variant of the receptor tend to have fewer bleedings during early pregnancy, fewer miscarriages, and give birth to more children.

Molecular analyses revealed that these women produce more progesterone receptors in their cells, which may lead to increased sensitivity to progesterone and protection against early miscarriages and bleeding.


Progesterone is a steroid sex hormone produced by the ovaries, placenta, and adrenal glands that is involved in pregnancy, menstrual cycle, libido, and embryogenesis in placental mammals (Taraborrelli 2015).

The progesterone receptor is encoded by the PGR gene on chromosome 11, and is most highly expressed in the endometrium. Binding of progesterone (or synthetic progestins) to the receptor mediates a gene regulation cascade that converts the endometrium to its secretory stage to prepare the uterus for implantation and helps maintain pregnancy.

Progesterone is also involved in stimulation of the mammary glands during pregnancy. It also has less well-understood roles as a neurosteroid in the brain (Baulieu and Schumacher 2000).

A polymorphic variant of PGR which carries the missense substitution V660L (rs1042838) in exon 4 and an Alu insertion between exons 7 and 8 occurs among present-day populations, reaching frequencies of up to ∼20% (sometimes called “PROGINS”; Rowe et al. 1995; Agoulnik et al. 2004; Terry et al. 2005; Liu et al. 2014).

A haplotype containing the V660L substitution and the Alu insertion as well as a synonymous mutation (H770H, rs1042839, exon 5) has been associated with preterm birth (Tiwari et al. 2015; Li et al. 2018), ovarian and endometrial cancer (Liu et al. 2014), migraine (Palmirotta et al. 2015), and endometriosis (Wieser et al. 2002).

Two functional studies have come to conflicting conclusions with respect to the responsiveness of variants of the receptor and their stability (Romano et al. 2007; Stenzig et al. 2010), perhaps depending on the particular variants and cell types used.

It has recently been noted (Li et al. 2018) that the valine to leucine substitution at position 660 occurs in a homozygous form in two Neandertal genomes sequenced to high coverage whereas it is not present in the genome of a Denisovan, an Asian relative of the Neandertals.

We find that it is also homozygously present in a third Neandertal genome and present in Neandertal genomes sequenced to low coverage (supplementary table S2, Supplementary Material online).

The association with preterm birth has been taken to indicate that it conferred an evolutionary disadvantage on Neandertals (Li et al. 2018) and raises the question why it has risen in frequency in modern human populations.

Here, we revisit the Neandertal progesterone receptor in the light of recent data.

The V660L variant occurs at frequencies between 2% and 22% among Europeans and Native Americans as well as in parts of Asia (fig. 1A). It sits on a DNA segment of at least 56 kb (r2 > 0.8) that is introgressed from Neandertals (fig. 1B, P = 0.02, Materials and Methods).

In addition to V660L, the Neandertal haplotype includes the H770H synonymous variant (rs1042839, r2 = 0.98) and the S344T missense variant (rs3740753, r2 = 0.95), both of which were polymorphic in Neandertals but do not occur in the high coverage Denisovan genome (supplementary table S2, Supplementary Material online).

The Alu element is embedded in the Neandertal haplotype but we find that V660L does not fully cosegregate with Alu insertion in the 1000 Genomes data set (r2 = 0.72).Fig. 1

Geographic distribution of V660L, introgressed Neandertal haplotypes and the Alu element in PGR. (A) Allele frequency of V660L (rs1042838) in 26 populations. Data from the phase 3 release of the 1000 Genomes Project. The African American populations (ASW, African Ancestry in Southwest United States; ACB, African Caribbeans in Barbados) have a lower frequency of V660L, similar to that in African populations, whereas North Americans with European ancestry (e.g., CEU: Utah Residents with Northern and Western European Ancestry) have frequency similar to European populations. (B) Similarity of present-day chromosomes carrying S344T+V660L+H770H with (n = 256) and without (n = 89) the Alu element to three high-coverage Neandertal genomes. In addition to the four polymorphisms indicated, data for 74 SNPs where a minor or absent allele among the Yoruba in the 1000 Genomes Project occurs three or more times among the three Neandertals. A gray box indicates that the major allele among the chromosomes with (above) or without (below) the Alu insertion matches the allele that occurs three or more times among the Neandertals. (C) Read depth for three high-coverage Neandertal genomes when aligned to the reference human genome (hg19). Note the symmetrical drop in read depth at the site for the Alu insertion in the Chagyrskaya Neandertal genome and a less pronounced drop in coverage in the Altai genome. (D) DNA fragments from the Chagyrskaya genome aligned to a DNA sequence carrying the Alu element around the 5′-end of the Alu element (chr11:100,911,793).
Geographic distribution of V660L, introgressed Neandertal haplotypes and the Alu element in PGR. (A) Allele frequency of V660L (rs1042838) in 26 populations. Data from the phase 3 release of the 1000 Genomes Project. The African American populations (ASW, African Ancestry in Southwest United States; ACB, African Caribbeans in Barbados) have a lower frequency of V660L, similar to that in African populations, whereas North Americans with European ancestry (e.g., CEU: Utah Residents with Northern and Western European Ancestry) have frequency similar to European populations. (B) Similarity of present-day chromosomes carrying S344T+V660L+H770H with (n = 256) and without (n = 89) the Alu element to three high-coverage Neandertal genomes. In addition to the four polymorphisms indicated, data for 74 SNPs where a minor or absent allele among the Yoruba in the 1000 Genomes Project occurs three or more times among the three Neandertals. A gray box indicates that the major allele among the chromosomes with (above) or without (below) the Alu insertion matches the allele that occurs three or more times among the Neandertals. (C) Read depth for three high-coverage Neandertal genomes when aligned to the reference human genome (hg19). Note the symmetrical drop in read depth at the site for the Alu insertion in the Chagyrskaya Neandertal genome and a less pronounced drop in coverage in the Altai genome. (D) DNA fragments from the Chagyrskaya genome aligned to a DNA sequence carrying the Alu element around the 5′-end of the Alu element (chr11:100,911,793).

The Neandertal haplotypes with and without the Alu element exist in all major populations of present-day non-Africans (fig. 1A;supplementary table S1, Supplementary Material online).

This suggests that the Alu insertion took place early after introgression of the haplotype into modern humans or that it was polymorphic among Neandertals and that at least two Neandertal haplotypes were transferred to modern humans.

To determine whether the Alu insertion was polymorphic among Neandertals we analyzed shotgun sequence data of the three high-coverage Neandertal genomes flanking the site of the Alu insertion.

If the insertion was homozygously absent in a Neandertal we expect the coverage to match the genomic average around the insertion site, as the reference human genome (hg19) to which the Neandertal sequences are aligned does not carry the Alu insertion.

In contrast, if the Alu element is homozygously present we expect the read depth to drop to near zero as short ancient DNA fragments fail to align. For one 60–80,000-year-old Neandertal genome from Siberia, coverage drops symmetrically to zero around the site of the Alu insertion (fig. 1C) and no fragments covering the Alu insertion site are seen, suggesting that the Alu element was homozygously present in this Neandertal.

We aligned the DNA fragments sequenced from this genome to the haplotype carrying the Alu insertion and found 20 fragments carrying the 5′-end of the Alu element as well as adjacent single-copy DNA sequences (fig. 1D, Materials and Methods).

In another ∼120,000-year-old Siberian Neandertal genome, a less pronounced reduction of the coverage was observed at the site of the Alu element. For that genome, we found 25 fragments carrying the Alu element and adjacent single-copy sequences and 40 fragments covering the Alu insertion site without the insertion, suggesting that this Neandertal was heterozygous for the Alu insertion.

In contrast, 36 and 0 fragments without and with the Alu insertion, respectively, were found in an ∼50,000-year-old Neandertal genome from Europe, suggesting that this individual homozygously lacked the insertion.

Thus, two variants of the Neandertal PGR haplotype existed among Neandertals, one with and one without the Alu element, and both were introduced into the gene pool of modern humans.

As the number of sequenced ancient modern human genomes increases, it is becoming possible to follow changes in the frequency of genetic variants over time in modern humans.

The oldest modern human individual available who carries the Neandertal-derived V660L variant is an ∼40,000-year-old individual from Tianyuan Cave, China (Yang et al. 2017). The V660L variant is then present in several Pleistocene genomes west of the Ural Mountains older than 10,000 years (fig. 2A; Reich 2019; see also Supplementary Movie) and becomes progressively more common in western Eurasia after that time (fig. 2B).

When more ancient genomes become available from East Asia, it will hopefully be possible to address why a corresponding increase is not seen there (fig. 1A).Fig. 2

Geographic distribution of ancient genomes carrying the Neandertal-derived V660L variant. (A) Ancient genomes older than 10,000 years. (B) Ancient genomes between 5,000 and 10,000 years old.

To determine whether the Neandertal haplotype influences phenotypic traits in modern carriers we searched for associations between V660L polymorphism and phenotypes among 452,264 Britons in the UK Biobank using the Gene ATLAS tool (Canela-Xandri et al. 2018).

Of 22 inpatient diagnoses related to pregnancy, childbirth and the puerperium (chapter XV of the International Classification of Diseases; ICD), we find a negative association between the Neandertal allele and “hemorrhage in early pregnancy” (ICD O20; OR = 0.83, P = 0.002, P(adjusted) = 0.044; fig. 3A). In the UK Biobank interview records, carriers of the Neandertal allele report less miscarriages (OR = 0.85, nominal significant at P = 0.009, although not when corrected for multiple testing; fig. 3A).

As a proxy for fertility, we use the number of full sisters and brothers, although only half of the individuals carrying one copy of the Neandertal allele would have a mother with the Neandertal variant.

Nevertheless, individuals carrying the Neandertal V660L allele have significantly more sisters (P = 0.0036; fig. 3B) than those carrying the ancestral allele, whereas there is no difference for brothers. Taken together, the increased number of sisters and the reduced risk of bleeding and miscarriages suggest that the Neandertal variant of PGR is associated with increased fertility.

Phenotypic consequences and relative expression levels associated with the V660L allele. (A) Odds ratios (OR) for hemorrhage in early pregnancy (ICD O20) and miscarriage for carriers of the V660L allele. (B) Numbers of full sisters and full brothers for the V660L allele. 95% confidence intervals in parentheses. Frequency of the V660 allele in the cohort is 16.5%. (C) Normalized effect sizes (NES) for 11 tissues where V660L is predicted to explain variation in expression levels of PGR mRNA (posterior probability of effect > 0.9). In all 11 tissues, the Neandertal allele is associated with higher expression; 95% confidence intervals in parentheses.
Phenotypic consequences and relative expression levels associated with the V660L allele. (A) Odds ratios (OR) for hemorrhage in early pregnancy (ICD O20) and miscarriage for carriers of the V660L allele. (B) Numbers of full sisters and full brothers for the V660L allele. 95% confidence intervals in parentheses. Frequency of the V660 allele in the cohort is 16.5%. (C) Normalized effect sizes (NES) for 11 tissues where V660L is predicted to explain variation in expression levels of PGR mRNA (posterior probability of effect > 0.9). In all 11 tissues, the Neandertal allele is associated with higher expression; 95% confidence intervals in parentheses.

To investigate if the V660L polymorphism affects the expression of the progesterone receptor, we use data from the Genotype-Tissue Expression project (GTEx). The eleven tissues with a posterior probability of an effect >0.9 (Han and Eskin 2012) are shown in figure 3C. We find that V660L is associated with higher mRNA expression of the progesterone receptor (P=–7.00e-51; meta-analysis across all tissues).

Orally administered progesterone has been shown to reduce the rate of spontaneous miscarriages and to improve fertility among women who have experienced bleeding in early pregnancy and recurrent miscarriages (Haas et al. 2019).

Given the role of progesterone in the maintenance of pregnancy (Taraborrelli 2015), some effect of the Neandertal PGR haplotypes, particularly their higher expression (fig. 3C), may explain their association with increased fertility and why they appear to have increased in frequency over time in Europe and the Americas (figs. 1 and 2).

This increase in frequency is in apparent contradiction to their association with preterm births (Tiwari et al 2015; Li et al 2018). However, we suggest that the Neandertal progesterone receptor variants may help maintain pregnancies that would otherwise be terminated, and that a consequence (or physiological trade-off) of this may be the association of the same variants with preterm live births.

There also seems to be no grounds to assume that the Neandertal versions of PGR posed a selective disadvantage to Neandertals. In fact, the association with higher numbers of live births might explain why some of these derived changes seem to have become frequent or fixed among Neandertals, although the smaller effective population size of Neandertals might have reduced the effectiveness of selection in Neandertals (Castellano et al 2014; Harris and Nielsen, 2016).

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The research was supported by the NOMIS Foundation and the Max Planck Society.

Reference

Svante Pääbo, Janet Kelso, Hugo Zeberg. The Neandertal Progesterone ReceptorMolecular Biology and Evolution, 2020; DOI: 10.1093/molbev/msaa119

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