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The field of genetics and genomics continues to advance at an incredible pace since the completion of the Human Genome Project. Now, thanks to rapid advances in sequencing technology and bioinformatics, we have sequenced hundreds of thousands of genomes from around the world, uncovering great genetic diversity and challenging us to understand the biologic relevance. Sequencing the exome (the protein-coding parts of the genome) of a patient with an undiagnosed condition as part of their clinical evaluation is now commonplace, although distinguishing the causative genetic change from the myriad other nonpathogenic variants remains challenging. As other technologies develop, we increasingly look beyond our DNA sequence to understand the regulation and function of the resulting RNA (transcriptome) and proteins (proteome) it encodes, integrating these layers to understand complex biological networks in health and disease. Even beyond human genetics, genomic technologies are making an enormous impact on pulmonary disease. In 2020, as the COVID-19 pandemic emerged, the SARS-CoV-2 virus was quickly sequenced and shared, in the spirit of open science pioneered by the Human Genome Project. Existing bioinformatic networks that already tracked other pathogens, such as influenza, were repurposed to disseminate the latest knowledge on the evolution of the virus as it spread around the world. Knowing the sequence, understanding its relation to other coronaviruses, and modeling the structure of viral proteins has been pivotal in enabling the development of vaccine candidates in record time. Against this backdrop, this chapter on the genetics of lung diseases could easily be out of date before it is even in print. Thus, it does not seek to be encyclopedic, but rather gives the reader a grounding in the principles of human genetics, an overview of current knowledge in Mendelian lung diseases, and a summary of recent progress in understanding genetic factors contributing to common lung conditions. The chapter outlines some of the emerging roles of epigenetic modifications and aims to give a vision of where the field is moving, concluding with exciting advances and prospects for genetically targeted therapies.


The sections below review the basics of genome organization, structure, and mutations; basic principles of inheritance; and mitochondrial mutations.

Genome Organization

The term genome refers to the genetic makeup of an organism (Table 7-1). Mammalian genomes are composed of deoxyribonucleic acid (DNA) and can be subdivided into a nuclear genome—DNA within the nucleus of each cell—and a separate circular genome housed within each mitochondrion. DNA has a double-helix structure. Each strand comprises four constituent bases—adenine (A), cytosine (C), guanine (G), and thymine (T)—that pair together, A with T and G with C. DNA needs to be replicated every time a cell divides. This strict base pairing ensures accurate copying of the DNA code.

TABLE 7-1Glossary of Genetic Terms

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