The Human Genome and Neonatal Care

The Human Genome Project and the Big Picture of Genomic Medicine

The Human Genome Project was an international effort that included a focus on identifying the chromosomal location of normal and disease-causing genetic variants. The international effort continues with some countries’ population-based studies applying whole genome or exome sequencing to tens of thousands of individuals, mostly in relatively high-resource countries with overrepresentation of communities with European ancestry. The Global Genomic Medicine Collaborative (G2MC) was formed in 2015 to facilitate implementation of genomic medicine worldwide to improve individual and population health, with the imperative for inclusion of geographic and population diversity. More global efforts in accumulating cohorts with extensive genomic information have begun, and the G2MC has prioritized the need for provider education programs, as this is likely to be a rate-limiting step in appropriate allocation and utilization of genomic testing.

By participating in collaborative efforts, clinicians and researchers have published studies of comprehensive views of genetic variation for thousands of individuals with type 2 diabetes, breast cancer, or traits such as height or birth weight. These collaborative international efforts have created the framework for one of the greatest successes of the Human Genome Project—that is, information generated relevant to the human DNA sequence and its variation, held in public trust with open access to the scientific community through dozens of accessible databases and analytic platforms.

One major hub for clinicians that contains both clinical and scientific descriptors of genetic findings on a disease basis is located on the website Online Mendelian Inheritance in Man ( www.ncbi.nlm.nih.gov/omim/ )—a comprehensive catalogue, updated daily, of more than 16,000 described genes, including the ever-growing total of over 7000 genes with phenotyping associations with a known molecular basis, and over 4500 genes with phenotype-causing mutation. The online version, a compendium of human genes and genetic phenotypes, also provides links to online resources that provide information about genetic variants, their associations with disease, and multiple other aspects of these genes such as their commonality across species and the differences in variant prevalence between populations of different ancestry, proteins and variations in protein structures, and which genes are in which biological pathways ( http://omim.org/help/external ; www.ncbi.nlm.nih.gov/omim/ ).

The Clinical Sequencing Exploratory Research (CSER) Consortium, funded by the National Human Genome Research Institute (NHGRI) and the National Cancer Institute (NCI), is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches. OMIM also includes a link to ClinVar, a freely accessible, public archive of reports of the relationships among human variations and phenotypes, with supporting evidence ( https://www.ncbi.nlm.nih.gov/clinvar/intro/ ). These and some of the other online tools that provide information about genetic variations and links to phenotypes are listed in Table 25.2 .

The Genome and Genomics

Genetics focuses on the study of single genes and their effects. Genomics is defined as the comprehensive study of the functions and interactions of all the genes in the genome. The Human Genome Project provided key information about the genome. It quantified the total number of base pairs (approximately 3 billion), defined genes, and provided more information about how genomic DNA might be classified. The genomic DNA of eukaryotic organisms includes exons (regions of DNA that are “expressed,” or translated into protein) and introns (intervening regions not translated into protein). Despite their apparent importance, exons account for less than 2% of the DNA in the entire genome. The regions outside of the exons are increasingly recognized to play critical roles in how and when the genes are expressed. The definition of what a “gene” is changes regularly as we learn more about distant regulatory elements, DNA modifications, chromatin structure, gene/gene interactions, exon skipping, post translational modification, and a host of other factors that determine what a “gene” does.

Understanding how conserved “noncoding” sequences influence human health and disease continues to be an important area of study. Even before the sequencing of the complete human genome, we knew that there were regulatory regions of the genome close to exons, sometimes called promotor regions. These are sites where transcription factors can bind to “turn on” or “turn off” a gene’s expression. The regulatory region is usually a different set of base pairs than the actual transcription start site where transcription of mRNA is initiated. We also know that certain combinations of mRNA result in “stop codons,” marking the point in the sequence where transcription stops ( Fig. 25.1 ).

https://www.ncbi.nlm.nih.gov/Class/MLACourse/Modules/MolBioReview/alternative_splicing.html

In addition to describing functional aspects of the genome, the origins of the human genome are also intriguing. Almost half of the genome is derived from foreign DNA. These entered the genome via germ cells as transposable element DNA, first described in maize by Barbara McClintock. Interestingly, we have learned that approximately 8% of the intronic base sequences are the products of human endogenous retroviruses (HERVs). The segments are DNA-based copies of their own viral RNA genetic material inserted into the human genome over millennia. Evidence is accumulating to suggest a potential functional role of these HERVs in numerous pathologies including neurodegenerative diseases, autoimmune disorders, and multiple cancers.

As our understanding of the genome has expanded, we know that many more RNAs and proteins can be made from the DNA in the genome. While approximately 20,000 protein-coding genes are known, the principle of alternative splicing (i.e., mRNA comprised of different exons from the same gene coding different proteins) increases the estimate of the number of proteins from the 20,000 one would imagine to well over 100,000. This is particularly important in the developing neuronal system, in which over 90% of multiexon genes are alternatively spliced throughout development ( Fig. 25.2 ).

https://www.ncbi.nlm.nih.gov/Class/MLACourse/Modules/MolBioReview/alternative_splicing.html

Mitochondrial Deoxyribonucleic Acid

Mitochondria are the energy-processing organelles within each cell. Each mitochondrion has its own genome, distinct from the nuclear genome and thought to arise from incorporation of bacterial DNA. The mitochondrial genome is approximately 16,500 base pairs in length and encodes 37 genes. A wide range of disorders have been associated with variation in mitochondrial sequence. In addition, because mitochondria reside in the cytoplasm and are not found in sperm, they have a unique pattern of maternal-only inheritance, in which mothers pass their mitochondria on to all their offspring, with the daughters then passing their mothers’ mitochondrial DNA on to subsequent generations. The knowledge that variants in mitochondrial DNA can cause disease plus the progress made in techniques for molecular and cellular manipulation have led to embryonic mitochondrial transplantation, where “healthy” mitochondria are transplanted into the cytoplasm of an early-stage embryo identified to have a lethal mitochondrial variant.

Variations in the Human Genome

Genetic variations are differences in the DNA sequence and structure among individuals. Variant types include single nucleotide polymorphisms (SNPs), copy number variants (CNV), insertions and deletions (indels), polymorphic repeats, and microsatellite variants. Additionally, there are differences in the amount of chromosomal material, termed aneuploidies.