Patric Jern

Over the past 5 to 7 million years, humans and chimpanzees have diverged in brain size, structure, and cognition despite high conservation of protein-coding genes. However, retroviral infections within host genomes have introduced numerous species-specific regulatory elements. Chimpanzees harbor lineage-specific PTERV1 endogenous retroviruses that are absent in humans, but their role in brain evolution has remained unclear. We performed an epigenomic analysis of PTERV1 insertions in chimpanzee neural organoids and found they are heavily DNA methylated, forming over 150 species-specific heterochromatin domains with the potential to influence gene regulation. We identified a chimpanzee-specific insertion on chromosome 19 that silences the long noncoding RNA LINC00662 through DNA methylation spreading. CRISPR-mediated deletion of this PTERV1 restored LINC00662 expression in chimpanzee induced pluripotent stem cells. We show that LINC00662 , a human-specific transcript expressed during brain development, plays a role in neuronal maturation, axon outgrowth, and neural organoid development. These findings reveal a mechanism by which endogenous retroviral insertions contributed to human-chimpanzee brain divergence.

Retroviruses that colonize the host germline can be passed on as inherited genetic variants. The koala ( Phascolarctos cinereus ) is currently experiencing germline colonization by two retroviruses, the koala retrovirus (KoRV) and phaCin-β. We analyze the integration site segregation and diversity of endogenous KoRV, phaCin-β, and the related phaCin-β-like in 111 pedigreed koalas from the San Diego Zoo Wildlife Alliance and seven European Zoos. The use of multigenerational pedigrees and the inclusion of health information for each individual koala reveal elimination of retroviruses from proto-oncogenes and the generation and spread of new germline integrations. Seven-hundred-and-fourteen integrations do not persist in the living population. For the 55 triads examined, 21 unique integrations identified in individual koalas are absent in their parents. Retroviral integrations associated with leukemia, fertility, and longevity are used to estimate genetic risk scores and develop a longevity breeding index to minimize neoplasia risk in the captive koala population.

Over the past 5 to 7 million years, humans and chimpanzees have diverged in brain size, structural complexity, and cognitive abilities despite high conservation of protein-coding genes. Notably, the endogenization and proliferation of retroviral infections within host genomes has introduced numerous species-specific regulatory elements that have the potential to influence gene regulation. However, the role of these endogenous retroviruses in hominoid brain evolution remains unclear. A burst of lineage-specific PTERV1 retroviruses recently invaded the chimpanzee genome but are absent in humans. We conducted an epigenomic analysis of PTERV1 insertions in chimpanzee neural organoids and found that they are heavily covered by DNA methylation, representing more than 150 species-specific heterochromatin domains with the capacity to influence gene regulatory networks. We identified one such chimpanzee-specific PTERV1 insertion on chromosome 19 that blocks the expression of the long noncoding RNA LINC00662, via DNA methylation spread to the adjacent genomic region. The expression of LINC00662 was restored in chimpanzee induced pluripotent stem cells when we deleted the PTERV1 insertion using CRISPR editing. We found that LINC00662, a human-specific RNA, is highly expressed in the developing brain and plays an important role in the posttranscriptional control of neuronal maturation, axon outgrowth, and neural organoid development. In summary, our findings describe how endogenous retroviral insertions contributed to the functional divergence of the human and chimpanzee brains. This provides a new mechanism by which retroviral pandemics influenced primate brain speciation.

Koalas (Phascolarctos cinereus) have experienced a history of retroviral epidemics leaving their trace as heritable endogenous retroviruses (ERVs) in their genomes. A recently identified ERV lineage, named phaCin-β, shows a pattern of recent, possibly current, activity with high insertional polymorphism in the population. Here, we investigate geographic patterns of three focal ERV lineages of increasing estimated ages, from the koala retrovirus (KoRV) to phaCin-β and to phaCin-β-like, using the whole-genome sequencing of 430 koalas from the Koala Genome Survey. Thousands of ERV loci were found across the population, with contrasting patterns of polymorphism. Northern individuals had thousands of KoRV integrations and hundreds of phaCin-β ERVs. In contrast, southern individuals had higher phaCin-β frequencies, possibly reflecting more recent activity and a founder effect. Overall, our findings suggest high ERV burden in koalas, reflecting historic retrovirus-host interactions. Importantly, the ERV catalogue supplies improved markers for conservation genetics in this endangered species.

Koalas ( Phascolarctos cinereus ) are subject to retroviral infections by the koala retrovirus (KoRV), resulting in accumulation of heritable endogenous KoRV in the koala germline. Like other vertebrates, koalas have experienced a history of retroviral epidemics leaving marks as endogenous retroviruses (ERVs) in their genomes; another recently identified ERV lineage, named phaCin-β , shows a pattern of recent, possibly current, activity with high insertional polymorphism in the koala population that predates the establishment of endogenous KoRV. We investigate geographic patterns of retrovirus activity, focusing on three distinct ERV lineages of increasing estimated ages from KoRV to phaCin-β and to phaCin-β-like , using a whole-genome sequencing dataset of 430 koalas produced by the Koala Genome Survey. We find thousands of ERV loci across the koala population and identify contrasting patterns of polymorphism. In the youngest established ERV-lineage (KoRV), we identify thousands of integrations among northern individuals. In the phaCin-β ERV lineage, which is slightly older yet with overlapping time of activity with KoRV, we observe hundreds of integrations in northern individuals. In southern koalas, however, phaCin-β loci are found at higher frequencies possibly reflecting a bottleneck effect. Overall, the findings suggest high ERV burden in koalas that represent historic retrovirus-host interactions. Importantly, the ERV catalogue supplies improved markers for population conservation genetics of this endangered species.

Endogenous retroviruses (ERVs) are inherited remnants of retroviruses that colonized host germline over millions of years, providing a sampling of retroviral diversity across time. Here, we utilize the strength of Darwin’s finches, a system synonymous with evolutionary studies, for investigating ERV history, revealing recent retrovirus-host interactions in natural populations. By mapping ERV variation across all species of Darwin’s finches and comparing with outgroup species, we highlight geographical and historical patterns of retrovirus-host occurrence, utilizing the system for evaluating the extent and timing of retroviral activity in hosts undergoing adaptive radiation and colonization of new environments. We find shared ERVs among all samples indicating retrovirus-host associations pre-dating host speciation, as well as considerable ERV variation across populations of the entire Darwin’s finches’ radiation. Unexpected ERV variation in finch species on different islands suggests historical changes in gene flow and selection. Non-random distribution of ERVs along and between chromosomes, and across finch species, suggests association between ERV accumulation and the rapid speciation of Darwin’s finches.

Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used snRNA-seq to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides a unique insight into the initiating events of the neuroinflammatory response in TBI, which has new therapeutic implications.

Retroviruses have left their legacy in host genomes over millions of years as endogenous retroviruses (ERVs), and their structure, diversity, and prevalence provide insights into the historical dynamics of retrovirus–host interactions. In bioinformatic analyses of koala ( Phascolarctos cinereus ) whole-genome sequences, we identify a recently expanded ERV lineage ( phaCin-β ) that is related to the New World squirrel monkey retrovirus. This ERV expansion shares many parallels with the ongoing koala retrovirus (KoRV) invasion of the koala genome, including highly similar and mostly intact sequences, and polymorphic ERV loci in the sampled koala population. The recent phaCin-β ERV colonization of the koala genome appears to predate the current KoRV invasion, but polymorphic ERVs and divergence comparisons between these two lineages predict a currently uncharacterized, possibly still extant, phaCin-β retrovirus. The genomics approach to ERV-guided discovery of novel retroviruses in host species provides a strong incentive to search for phaCin-β retroviruses in the Australasian fauna.

Endogenous retroviruses (ERVs) are inherited remnants of past retroviruses that colonized host germline over millions of years, providing a sampling of retroviral diversity across time. The utility of ERVs as markers of host genome evolution is augmented by their ability to reveal historic retrovirus-host interactions, given that ERVs are examples of active retroviruses at the time of germline invasion. Here, we utilize the strength of Darwin’s finches, a system synonymous with evolutionary studies, for investigating ERV history, revealing recent retrovirus-host interactions in natural populations. By mapping ERV variation across all species of Darwin’s finches and comparing with outgroup species, we highlight geographical and historical patterns of retrovirus-host occurrence, utilizing the system as a natural model for evaluating the extent and timing of retroviral activity in hosts undergoing adaptive radiation and colonization of new environments. We found shared ERVs among all samples indicating retrovirus-host associations pre-dating host speciation, as well as considerable ERV variation across populations of the entire Darwin’s finches’ radiation. Unexpected ERV variation in finch species on different islands suggest historical changes in gene flow and selection. Non-random distribution of ERVs along and between chromosomes, as well as across finch species, suggests association between ERV accumulation and the rapid speciation of Darwin’s finches.