25 May 2018

In evolution, there is no free lunch. In other words, a good brain exacts its price. According to a May 23 study in Cell Systems, some of the same genetic adaptations that bestowed the cerebral cortex on humans also may have opened the door to diseases of aging. Researchers led by Han Liang at the University of Texas MD Anderson Cancer Research Center in Houston identified nearly 100 neuron-specific enhancers that rapidly evolved after the chimpanzee-human divergence. Though these enhancers appear to benefit brain development, they also reside near susceptibility loci for diseases that strike after the glow of fertility has faded, including Alzheimer’s and Parkinson’s. Notably, one enhancer promoted the expression of genes normally suppressed by REST, a transcriptional repressor that protects against AD.

“This creative study gives us a new way to look at the genetics of neurodegenerative disease,” commented Bruce Yankner of Harvard Medical School in Boston. “Often in genetics, we consider highly conserved elements as the most important, but here they have taken the opposite approach.” He added that the findings help explain why diseases such as AD are uniquely human.

The primary driver of evolution is reproductive success, but adaptations that promote survival into the fertile years come with no guarantee of benefit in the golden years. Just the opposite, posits the hypothesis of antagonistic pleiotropy. First suggested by none other than Darwin himself, and further honed by George Williams, the hypothesis’s central premise is that adaptations geared toward reproductive success come at a price later in life, offering an explanation for the existence of aging-related disease (see Williams, 1957). These unintended consequences would only manifest in species that live long past their reproductive years, including humans (Finch, 2010). So far, scant evidence exists to support this hypothesis.

Evolution’s Toll. Enhancers active in neural tissues evolved rapidly in humans (top), but also disproportionately reduced cancer survival (bottom left) and associated with disease risk loci (bottom right). [Courtesy of Chen et al., Cell Systems, 2018.]

First author Han Chen and colleagues set out to test the idea by identifying recently evolved genetic adaptations, and asking if they related to diseases of aging. Specifically, they looked for human-specific enhancer sequences, as the bulk of genetic differences between chimpanzees and humans lie in gene regulatory elements, rather than protein-coding sequences. The researchers searched an enhancer database generated by the FANTOM project, which contains more than 32,000 annotated human enhancers with tissue-biased expression patterns (Andersson et al., 2014). They then searched for the enhancer sequences in other primate genomes, and selected those that had evolved since humans diverged from chimps. The researchers found that more than three-quarters of these recently evolved enhancers were most active in neuronal stem cells and neurons.

In all, Chen identified 93 human-specific enhancers activated in nervous tissues (hEANTs). The genes closest to these hEANTs were enriched for those involved in axon guidance, a key function in the developing human brain. Statistical genomic analyses suggested that these neural enhancers likely appeared in the human genome due to the forces of positive selection.

The researchers next asked the big question: Did some of these beneficial adaptations also make humans more vulnerable to diseases of aging? Because they specialize in cancer, they first dove into the Cancer Genome Atlas database, which contains RNA sequencing data from 23 cancer types. Among the RNA sequences in the database are those for transcribed enhancer sequences. Researchers can use these noncoding transcripts as proxies for enhancer activation, because their existence implies that the enhancer sequence is accessible to transcription factors and other regulatory proteins. Among the more than 7,000 enhancers active across the cancer types, nearly a third were associated with patient survival time. Strikingly, nearly two-thirds of hEANTs were associated with survival, suggesting these enhancers were doubly enriched for their influence on cancer.

Liang proposed that these hEANTs, which were primarily active in neural tissues, could cause cancer in other organs in the body if they become aberrantly active there later in life. Thus, the hEANT-controlled genes that mediate brain development could be distinct, both in space and timing of expression, from those that ultimately promote disease, Liang told Alzforum. “The compromising effect may or may not be associated with the adaptive effect,” he said.

What about other diseases of aging? The researchers investigated if the hEANTs resided near genes linked to susceptibility loci identified in genome-wide association studies (GWAS) for five common diseases of aging: AD, PD, hypertension, Type 2 diabetes, and osteoporosis. Indeed, they found 11 hEANTs—more than triple the number expected by chance—that fit the bill. In contrast, genes implicated in childhood diseases had fewer nearby hEANTs than expected. Genes involved in general aging processes were barely associated with hEANTs, suggesting that these enhancers were specifically enriched for genes involved in aging disease.

To understand how each hEANT might influence disease, the researchers next constructed modules of genes co-expressed with each hEANT, using gene expression data from brain tumors, as well as normal brain tissue from the GTEx consortium (Oct 2017 news). One of the most extensive modules consisted of 121 genes co-expressed with a hEANT on chromosome 8, dubbed hEANT-8. Genes in the module associated with a panel of neurological diseases, including AD, and 14 of them contained a binding site for REST, a transcriptional suppressor known to protect against AD (Mar 2014 news and Alzforum Timeline). The pattern of hEANT-8 expression was the opposite of REST and its targets, suggesting that this enhancer could turn on the very genes that are normally suppressed by REST. hEANT-8 expression was also elevated in brains of people with AD, while, as demonstrated in previous studies, REST expression was reduced.

How is it that hEANT-8 and REST share some of the same targets? Liang proposed that hEANT-8 could enhance expression of a master regulator, such as a transcription factor or miRNAs, that also controls REST targets. Yankner, who first reported REST’s protective effects against AD, added that many of REST’s targets play important roles in brain development, while others influence neurodegenerative disease. He wondered whether REST itself might also regulate hEANT-8 activity, thus completing a gene-regulation loop.

Though the REST pathway had already been discovered, Yankner said that the hEANTs identified by Liang and colleagues could make prime hunting grounds for other disease-related genes and pathways. Indeed, Liang told Alzforum that he is taking this approach to study cancer-related pathways. Also, given the small number of hEANTs, researchers could search for disease-associated variants in them, Yankner said.

Philip De Jager of Columbia University in New York commented that the discovery of these human-specific neural enhancers was fascinating, and agreed that they could be a resource for further study of disease mechanisms. However, he was less convinced by the data implicating them in diseases of aging, noting that more data is needed to move beyond correlation.

The findings offer a potential explanation for why humans seem uniquely vulnerable to AD and other aging diseases, Yankner said. The negative manifestations of these evolutionary adaptations may only have emerged over the past century, as human lifespans extended dramatically, he said. De Jager agreed: “In evolutionary terms, humans were not designed to live past 80,” he said.

Cynthia Lemere of Brigham and Women’s Hospital in Boston wondered whether the newly evolved enhancers could explain the extent of AD pathology that develops in humans compared to nonhuman primates. She pointed out that while most nonhuman primate species develop Aβ pathology, the incidence of tau pathology and cognitive decline is inconsistent across species. “Most scientists view NHPs as a model of early AD,” she wrote. “Could it be possible that these animals do not develop full-blown AD because they do not have the same evolutionarily derived enhancers?”

If the enhancers promote AD in people, do they negate the importance of animal models to study the disease? No, Yankner and Liang agreed. Though by definition the hEANTs do not exist in mice or monkeys, the genes they control do. For example, REST and its targets are expressed in mice, Yankner said. Therefore, researchers could use hEANTs to identify potential disease-related genes and pathways, which could then be elaborated in model organisms.—Jessica Shugart

Comments

1. • Cynthia Lemere
     Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School
   • Posted: 29 May 2018

   I just read through this interesting paper and I am impressed by the data supporting George Williams’ antagonistic pleiotropic theory of human evolution, which proposes that adaptive evolutionary changes that protect/facilitate reproduction early in life will also enhance aging-related changes. It is interesting that the neuronal stem cell-expressed enhancers and neuron-expressed enhancers (noncoding regulatory elements) showed the fastest relative evolutionary rate on the B4 branch of the primate evolutionary tree, which reflects human-specific evolution. It is also interesting that these human-specific enhancers activated in nervous tissues (hEANTs) seem to be associated with (or near genes associated with) aging-related diseases such as cancer, Alzheimer’s disease, Parkinson’s disease, hypertension, Type 2 diabetes, and osteoporosis.

   The findings raise some interesting questions:

   • Does the fact that the age of puberty is earlier now than it was 20–50 years ago, suggest that aging-related changes are also accelerated, even though the lifespan has increased?
   • Nonhuman primates (NHPs), e.g., chimpanzees, orangutans, rhesus macaques, African green monkeys (including vervets), squirrel monkeys, marmosets, and tamarins all develop amyloid-β deposits—and in many cases, both as plaques and vascular amyloid. There is also some evidence for cognitive decline with aging in at least in some of these animals. Tau pathology is less consistent but has been shown in some NHPs (naturally or induced with environmental toxins). However, most scientists view NHPs with AD pathology as “models of early AD.” Could it be possible that these animals do not develop full-blown AD because they do not have the same evolutionarily-derived enhancers?
   • It is interesting that the hEANTs are associated with cancers, but do they only associate with cancers of the nervous system or with cancers of the blood and peripheral organs, such as liver, kidney, etc.? There is considerable interest in whether cancer and AD share any common mechanisms. 
   View all comments by Cynthia Lemere

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References

News Citations

1. Gene Expression Map of Human Body Gives Value to Variants 23 Oct 2017
2. No REST for Weary Neurons: Protective Factor Stems Cognitive Decline 19 Mar 2014

Paper Citations

1. Finch CE. Evolution in health and medicine Sackler colloquium: Evolution of the human lifespan and diseases of aging: roles of infection, inflammation, and nutrition. Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1718-24. PubMed.
2. Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, Chen Y, Zhao X, Schmidl C, Suzuki T, Ntini E, Arner E, Valen E, Li K, Schwarzfischer L, Glatz D, Raithel J, Lilje B, Rapin N, Bagger FO, Jørgensen M, Andersen PR, Bertin N, Rackham O, Burroughs AM, Baillie JK, Ishizu Y, Shimizu Y, Furuhata E, Maeda S, Negishi Y, Mungall CJ, Meehan TF, Lassmann T, Itoh M, Kawaji H, Kondo N, Kawai J, Lennartsson A, Daub CO, Heutink P, Hume DA, Jensen TH, Suzuki H, Hayashizaki Y, Müller F, Forrest AR, Carninci P, Rehli M, Sandelin A. An atlas of active enhancers across human cell types and tissues. Nature. 2014 Mar 27;507(7493):455-461. PubMed.

Other Citations

1. Alzforum Timeline

External Citations

1. Williams, 1957

Further Reading

News

1. Alzheimer’s Brains Mottled with Epigenetic Changes 21 Aug 2014
2. Epigenetic Alterations Mark Alzheimer’s Disease Genes 7 Nov 2014