key: cord-0328000-kmgsyf2b authors: Chen, Zhongbo; Reynolds, Regina H.; Pardiñas, Antonio F.; Gagliano Taliun, Sarah A.; van Rheenen, Wouter; Lin, Kuang; Shatunov, Aleksey; Gustavsson, Emil K.; Fogh, Isabella; Jones, Ashley R.; Robberecht, Wim; Corcia, Philippe; Chiò, Adriano; Shaw, Pamela J.; Morrison, Karen E.; Veldink, Jan H.; van den Berg, Leonard H.; Shaw, Christopher E.; Powell, John F.; Silani, Vincenzo; Hardy, John A.; Houlden, Henry; Owen, Michael J.; Turner, Martin R.; Ryten, Mina; Al-Chalabi, Ammar title: The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases date: 2022-04-29 journal: bioRxiv DOI: 10.1101/2022.04.29.490053 sha: e6b6ec7b8e2d6e4cf78316d13b5b8190d5241000 doc_id: 328000 cord_uid: kmgsyf2b Background Humans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how common variants associated with neurodegenerative disease risk are maintained by natural selection in the population despite their deleterious effects. In this study, we aimed to quantify the genome-wide contribution of Neanderthal introgression and positive selection to the heritability of complex neurodegenerative disorders to address these questions. Methods We used stratified-linkage disequilibrium score regression to investigate the relationship between five SNP-based signatures of natural selection, reflecting different timepoints of evolution, and genome-wide associated variants of the three most prevalent neurodegenerative disorders: Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Results We found a significant depletion of positively-selected SNPs in the heritability of Parkinson’s disease, raising the possibility that these variants may modulate disease risk, in addition to conferring an evolutionary advantage. For Alzheimer’s disease and amyotrophic lateral sclerosis, common deleterious disease variants are unlikely to be maintained by positive selection. There was no enrichment of Neanderthal introgression in the SNP-heritability of these disorders, suggesting that Neanderthal admixture is unlikely to have contributed to disease risk. Conclusions These findings provide insight into the origins of neurodegenerative disorders within the evolution of Homo sapiens and addresses a long-standing debate, showing that Neanderthal admixture is unlikely to have contributed to common genetic risk of neurodegeneration in anatomically-modern humans. Encephalisation and the evolution of complex human-specific traits are thought to have increased the susceptibility of Homo sapiens to disorders of the brain compared to their aged non-human primate counterparts. [1] [2] [3] This is seen in Alzheimer's and Parkinson's disease, which have not been observed naturally on a pathological or phenotypic level in non-human species. 1 2 Likewise, unique motor dysfunction in amyotrophic lateral sclerosis (ALS) supports the selective vulnerability of the highly-developed corticomotoneuronal system in humans. [4] [5] [6] Human-lineage-specific genomic sequences have been shown to be enriched for brain-specific elements and risk loci for neurodegenerative disorders. 7 Thus, while positive natural selection has driven human adaptive evolution, 8 it may be possible that the same selected variants also influence the risk of neurodegenerative disease. It is not known whether this neuro-vulnerability arose after divergence from other species or whether it represents a more recent phenomenon, characteristic of modern-day humans over other hominids. As anatomically-modern humans migrated out of Africa 50 to 100 thousand years ago, they interbred with archaic hominins including Neanderthals. 9 As a result, Neanderthal DNA accounts for approximately 1-4% of the modern Eurasian genome. [10] [11] [12] While most Neanderthal DNA experienced purifying selective pressures, 13 positive selection of these archaic alleles may have contributed to modern human adaptation to the non-African environment 14 through modulating dermatological 13 , immunological 15 16 and metabolic function. 17 18 T hese introgressed Neanderthal alleles have also been implicated in contributing to the risk of some conditions, including actinic keratosis, depression and obesity. 19 It remains unclear how much Neanderthal admixture has affected our risk of neurodegenerative disorders. While Neanderthal single nucleotide polymorphisms (SNPs) may be associated with "neurological" phenotypes through electronic health records of European patients, these nervous system traits were not representative of neurodegenerative diseases. 19 More recently, one study aimed to address the complex nature of medicallyrelevant traits and the genome-wide influence of Neanderthal admixture using UK Biobank data. 20 This found that introgressed variants were depleted for heritability of high-level cognitive traits. 20 Thus, to quantify the contribution of Neanderthal admixture to the heritability of neurodegenerative diseases and to examine whether natural selection maintains common genetic risk of these disorders, we tested the relationship between alleles associated with Alzheimer's disease 21 , ALS 22 and Parkinson's disease 23 from recent genome-wide association studies (GWAS) with SNP-based signatures of natural selection. 24 Using stratified-linkage disequilibrium score regression (LDSC), we found that there was a significant depletion of SNP-heritability for Parkinson's disease in alleles most subjected to Neanderthal introgression and positive selection. There was no significant enrichment of Neanderthal introgression or positive selection in the SNP-heritability of Alzheimer's disease. Variants from more recent selective sweeps were nominally enriched for association with ALS heritability, while SNPs from older selective sweeps showed a trend for depletion of ALS heritability. Thus, positive selection is unlikely to have played a significant role in the maintenance of common deleterious variants in the genetic architecture of these neurodegenerative diseases. Heritability is defined as the fraction of a trait that is explained by inherited genetic variants in a given environment, and is important for understanding the biology of disease. 25 More specific to stratified-LDSC, narrow-sense heritability is defined as the proportion of phenotypic variance that can be attributed to variation in the additive effects of genes. 26 Stratified-LDSC analysis estimates the SNP-based heritability (h 2 SNP ) of complex traits stratified across different annotations using GWAS data. 27 28 Thus, we were able to use stratified-LDSC to assess the enrichment and depletion of common-h 2 SNP of complex neurodegenerative diseases for metrics of Neanderthal introgression and positive selection. 24 For the metric of Neanderthal introgression, we used the average posterior probability of each human haplotype being the result of Neanderthal admixture estimated by comparing human and Neanderthal genomes (LA). 13 24 We used four metrics of positive selection: integrated haplotype score (iHS), composite of multiple signals (CMS), cross-population extended haplotype homozygosity (XP-EHH), and composite likelihood ratio (CLR). These metrics were chosen to reflect the different timeframes of the selective processes used and described in previous analyses. 24 iHS measures the amount of extended haplotype homozygosity at a given SNP in the ancestral allele relative to the derived allele and estimates positive selective sweep. 8 CMS identifies the regions under positive selection by combining long-range haplotypes, differentiated alleles and high frequency derived alleles. 29 Both iHS and CMS detect more recent selective sweeps in the last 30,000 years. 8 29 XP-EHH compares two populations to detect an allele that has reached fixation in one population but remains polymorphic in another, identifying alleles that have undergone different selective pressures since population divergence. 30 Lastly, CLR detects incomplete selective sweeps, quantifying the relative influence of recombination and selection and corrects for background selection. 31 It can thus detect older signals from ~60,000 to 240,000 years ago. 24 We did not use any other 24 33 Further, we transformed the absolute iHS and -log 10 XP-EHH metrics to ensure that all metrics were on a common scale, in which larger values indicate stronger effect of selection or increased probability of introgression. We used stratified-LDSC v.1.0.1 (https://github.com/bulik/ldsc/wiki) to test whether these natural selection metrics contribute significantly to heritability of neurodegenerative disease. All natural selection metrics were annotated to the ~9,997,000 SNPs present in the baseline LDSC model (v.2.2), which only includes SNPs with a minor allele frequency of more than 5%. Binary annotations were generated from the natural selection metrics, with thresholds at the top 2%, 1% and 0.5% of the genome-wide values of each metric in the full set of baseline SNPs. 24 This centile approach was used in previous studies due to difficulties defining the thresholds for selection. 24 Annotations were then added individually to the baseline LDSC To quantify the contribution of Neanderthal introgression and positive natural selection to the heritability of three neurodegenerative disorders, we used stratified-LDSC to assess enrichment or depletion of the h 2 SNP of Alzheimer's disease, ALS and Parkinson's disease for each SNP-based signature of natural selection. For all analyses, we reported a two-tailed coefficient p-value that tested whether Table 2 ). After correction for multiple testing, we found a significant depletion of Parkinson's disease Humans are particularly vulnerable to neurodegeneration. 1 2 For example, in ALS, the most frequent neurodegenerative disease of mid-life, motor neurone degeneration results in disruption of multiple motor functions that are key to survival, and therefore of importance for evolutionary adaptation. 37 Any genetic variation predisposing to motor neurone degeneration might therefore be expected to be under major negative selection pressures. Thus, several possible evolutionary explanations may exist for common alleles contributing to neurodegenerative disease risk to persist in the population despite their deleterious effects. First, any genetic variation predisposing to disease could have a corresponding benefit and therefore be positively selected. This is a mechanism by which the persistence of Neanderthal-derived sequences in the modern Eurasian human genome has been explained. 13 For example, a Neanderthal haplotype associated with protection against severe forms of SARS-CoV-2 infection (and other RNA viruses) is also linked to Alzheimer's disease risk. 38 39 40 Alternatively, deleterious variants in LD with an advantageous allele may have hitchhiked during positive selection, rising in frequency in the population. 41 This would be consistent with the proposed Northern founders of the p.91D>A SOD1 variant in ALS 42 and the pathogenic C9orf72 hexanucleotide repeat expansion associated with ALS and frontotemporal dementia. 43 44 Secondly, because neurodegenerative disorders are diseases of ageing, any genetic susceptibility might act after child-rearing years, and therefore outside the age window in which negative selection pressure could have an impact on allele frequency. 45 In this scenario, the negative effect of the genetic variant is mitigated by the timing of neurodegeneration. Thirdly, neurodegenerative diseases might result from multiple rare variants, each unique in the affected person, and therefore be too rare for selection to have a significant impact. 46 With the increased availability of high-depth next generation sequencing, many rare variants have now been found to be associated with ALS 22 47 48 , Parkinson's disease 23 49 and Alzheimer's disease 50 51 , but common variants also contribute to risk. To address these hypotheses of how natural selection may have led to the persistence of common genetic risk variants of neurodegenerative disorders, we used stratified-LDSC to test the relationship between neurodegeneration-related SNPs and SNP-based signatures of natural selection. Parkinson's disease h 2 SNP was depleted of introgressed Neanderthal SNPs. This observation is consistent with a recent study using UK Biobank data that showed introgressed variants were depleted for contribution to the heritability of most complex traits. 20 We also found no significant enrichment of Alzheimer's disease or ALS h 2 SNP in SNPs associated with Neanderthal admixture. Together, these findings suggest that negative selection likely purged some introgressed alleles that influence Parkinson's disease risk, while it may be possible that introgressed variants conferred no overall effect for Alzheimer's disease or ALS. Thus, Neanderthal admixture is unlikely to have maintained the common genetic variant architecture of these neurodegenerative diseases in modern humans. Positive selection is seen as the main evolutionary mechanism for adaptation to a new environment. 52 In this situation, the beneficial allele sweeps to high frequencies and towards fixation (defined as 100% frequency) together with other variants on the same haplotype, reducing the population genetic diversity in a selective sweep. 52 55 Given the potential contribution of positive selection to ALS h 2 SNP is more recent, it could be hypothesised that the disease we see today is a unique disorder of anatomicallymodern humans. This means that the development of traits unique to modern humans, such as manual dexterity and complex tool use may also be accompanied by a vulnerability to motor neurone degeneration or by their functional complex failure. 37 It is also worth noting that a degenerative myelopathy has been described in other species such as dogs 56 This study has several limitations. Firstly, our analyses only studied individuals of European ancestry while Neanderthal introgression also occurred in non-European populations. Secondly, the h 2 SNP estimates using stratified-LDSC analysis are limited by the quality of LD information underpinning the heritability calculations 28 and the sample size of the GWAS, although we attempted to use only well-powered studies. LDSC also does not take into account the major histocompatibility complex region while Neanderthal alleles have been shown to play a role in modern immune function, thus missing those variants with pleiotropic effects in the nervous system. 15 Thirdly, each metric of natural selection and Neanderthal admixture has its own strengths and shortcomings and our analysis is limited by these measures. 52 However, we attempted to overcome this issue by using a range of SNP-based signatures. 24 Lastly, this analysis did not take into account structural variants, short tandem repeats or other repetitive genomic elements that may have been acquired through positive selection. A recent study showed a number of repeat elements have risen ab initio in Homo sapiens which may have implications for positive selection in disease given that these are the most mutable regions of the genome. 57 In this analysis, we quantified the contribution of positive selection and Neanderthal introgression to the heritability of Alzheimer's disease, ALS and Parkinson's disease using stratified-LDSC. We found no significant enrichment of Neanderthal introgression in the SNP-heritability of these neurodegenerative diseases. We also found that genomic regions with positive selection were depleted in heritability of Parkinson's disease with no evidence for the contribution of positive selection in Alzheimer's disease heritability. This suggests that positive selection does not maintain common risk variants for these disorders in the population even after controlling for background selection. Variants from more recent selective sweeps were nominally enriched for association with ALS heritability, while SNPs from older selective sweeps showed a trend for depletion of disease association. This provides further insights into the evolution of the genetic architecture of these disorders. Patient consent for publication: Not applicable. Ethics approval: This study does not involve human participants. All data relevant to the study are included in the article or uploaded as supplementary information. C ode is available from: https://github.com/RHReynolds/als-neanderthalanalysis. The Exceptional Vulnerability of Humans to Alzheimer's Disease Parkinson's disease: Is it a consequence of human brain evolution? Movement disorders : official journal of the Movement Evolution of neurodegeneration Amyotrophic lateral sclerosis (ALS): a phylogenetic disease of the corticomotoneuron? 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