These are engaging stories, given a narrative structure that no doubt hides a much messier progression of investigation, but Hariharan eschews hype or dramatisation and stays close to the science. The medical motivation and the human consequences are always clear, and Hariharan keeps the excitement informative:
"Wouldn't it be wonderful if we could somehow edit Sita's blood genome and restore the problematic G in her HBB gene back to a T? We would no longer need to kill Sita's bone marrow stem cells and replace them with someone else's stem cells. We could simply extract some bone marrow stem cells from Sita, kill her remaining bone marrow cells, edit the genomes in the extracted cells, and inject them back into her."
Along the way these stories introduce the basics of genetics and genomics, from Mendelian inheritance, cross-over and suchlike to the more involved details of exon-splicing and gene repair; they also explain techniques such as shotgun sequencing, stochastic modelling, and CRISPR gene editing. This doesn't assume any background knowledge, and was almost all familiar to me, but Hariharan's presentation is brisk. Each of the cases also involves specific genes, and examines different ways in which things can go wrong.
"The vast expanse of the genome is sparsely dotted by exons carrying gene recipes. These recipes account for a paltry 1-2% of the entire genome. The remainder of the genome comprises introns and regions between genes, neither of which carry recipes. It would appear, therefore, that genomic variants in these regions are inconsequential. But Sita's story tells us otherwise.
Genomic characters in the introns guide the recipe execution process as it jumps from one exon to the next. Variants here could well confuse these jumps. And a jump gone awry could well yield a dramatically different recipe, as seems to be the case with Sita.
Indeed the HBB gene is notorious for jumps gone awry on account of such intronic characters. For instance, 20% of the beta-thalassemia cases in China are caused by a variant sitting deep inside the second intron of HBB."
Accompanying this is the medical and biological detail needed to understand the specific cases. These touch on the structure of the retina, the operation of the heart, developmental chirality, the mesothelium, the progression of somatic mutations, and so forth.
Genomic Quirks would be a solid read for someone with no background at all in genetics, but not an impossible one — and well motivated for anyone interested in medical applications. In general Hariharan finds a good balance between broader background and the details of individual cases; he also gives clear explanations, using calm but effective colour diagrams. Working together, the nine stories in Genomic Quirks make an engaging introduction to how genomics is changing modern medicine.
Note: this is a high quality hardcover volume, with nice paper, and has been properly edited.
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