Once again, the flood of rare variants. Deep sequencing studies have revealed an unexpected plethora of rare variants, i.e. genetic variants that can only be found in few or even single individuals. While the genetic architecture of more common genetic variants, so-called Single Nucleotide Polymorphisms (SNPs) is well known through the HapMap project, the role of rare variants identified with recent sequencing studies is difficult to interpret. Basically, for an individual variant it is difficult to establish whether this variant is disease-causing or disease-related based on the frequency in cases. Establishing association at the same level of statistical significance as required for SNPs is difficult given that much larger samples are needed. Furthermore, protein prediction algorithms have their limitations and might not be able to discriminate an accidental from a causal variant, given that every individual might be homozygous or compound homozygous for gene-disrupting variants in at least three genes. We are drowning in a flood of rare variants and cannot distinguish pathological from benign variants very well yet. Continue reading
Man and ape. Comparative genomics is relating the differences between species in the genome to the phenotype. When the first comparisons between human and chimpanzee were published in 2005, neuroscientists were excited that this comparison would show what makes our brain human. A glance at the genes clusters that rapidly evolved during human-specific evolution was sobering. Many of the genes that rapidly evolved are immune-regulatory genes, highlighting our constant struggle with some parasites, bacteria and viruses and our arrangement with the microbiome, the cloud of microbes contribute ten times as many cells to our bodies than we do. Prominent genes such as FOXP2, a gene found to be disrupted in patients with developmental language problems, and most other brain genes barely show up as a group in comparative genomics.
Segmental duplications and human evolution. Recent human evolution did not only leave traces at the single-base pair level that allows for the discovery of individual sequence differences but also larger structural genomic variants including segmental duplications. Recurrent microdeletions such as the 15q13.3, 16p13.11 or 15q11.2 microdeletions occur relatively frequently because the genomic sequence of these deletions is located between segmental duplications (Figure 1). These segmental duplications are so similar that the DNA replication machinery sometimes mistakes one duplication for the other (e.g. the “right flanking duplication” for the “left flanking duplication”). Thereby, the intervening sequence is either deleted or duplicated. Segmental duplications are relatively human-specific, for example a paralogue region for the 15q13.3 microdeletion is not present in rodents. Even in chimpanzees, the segmental duplications that give rise to Prader-Willi-Syndrome, Williams-Syndrome or Spinal Muscular Atrophy are not present, indicating that something very human-specific must have happened here that resulted in these segmental duplications, which give rise to so-called genomic disorders. While many of the epilepsy genes identified through family studies including SCN1A or GABRG2 are conserved in animals, microdeletions are not.
The SRGAP2 story. Two recent publications on the SRGAP2 gene illustrate the problems with reasoning around the human-specific changes. Saitsu and colleagues describe a female patient with epileptic encephalopathy and a balanced translocation in SRGAP2, a gene highly expressed in the developing forebrain. Balanced translocations are very rare and might provide insight into monogenic epilepsy syndromes. The function of SRGAP2 is still unknown. The second paper by Dennis and collaborators describes the evolution of the SRGAP2 family, hypothesizing that the evolution paralleled neocortical expansion at the transition of Australopithecus to Homo.
How human is our SRGAP2? While the suggestion that disruption of a human-specific gene results in West Syndrome carries some appeal, comes with an almost philosophical flaw. Epileptic encephalopathy, a severe neurodevelopmental disease, may be conceptualized as a disruption of basic cellular or network processes, e.g. large malformations, neurometabolic disorders or fundamental disruptions of synaptic function rather than defects in the subtle differences between man and ape that make us human. In fact, the Toronto Database of Genomic Variants lists several intragenic deletions and duplications in SRGAP2, suggesting that disruptions of this gene may be seen in apparently healthy individuals. Possibly, the genetic architure in SRGAP2 might predispose to deletions, duplications or more complicated rearrangements that even result in balanced translocations. Evolution has merely generated a complex human-specific gene prone to recombination events rather than a genuine epilepsy gene.
Evolutionary genomics and EuroEPINOMICS. So-called hotspot microdeletions including variants at 15q13.3, 16p13.11, 15q11.2 are the immediate result of recent genomic changes that allowed us to be human. Segmental duplications rather than changes on the base-pair level might have been the main driver for human evolution, and the occurence of microdeletions may be conceptualized as a “trade-off” for the fragile human genomic architecture. Microdeletions already help us explain approximately 3% of cases of epilepsy. It can be hypothesized that similar effects on a smaller genomic level are still to be discovered and may help explain additional genetic findings seen in epilepsy patients.