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Human Genetics and Patterns of Inheritance
The Human Genome Project was completed on October 21, 2004, and provided the primary structure (nucleotide sequence) of all chromosomes. However, in the nearly 150 years preceding this breakthrough, there were major discoveries that were equally relevant. Gregor Mendel, known as the father of modern genetics, described the most basic modes of inheritance and provided an early understanding of human genetic variability. The double helix structure of DNA was described in the middle of the 20th century by James Watson and Francis Crick. Genome sequencing, made possible in part by the discovery of the polymerase chain reaction technique by Mullis and colleagues and sequencing reactions by Sanger and Coulson, helped bring the human genome out of the laboratory to the bedside. In this chapter, we link the principles of meiosis and mitosis to emerging clinical practice in genomic medicine. We illustrate errors in mitosis and meiosis that lead to medical conditions familiar to prenatal diagnosticians and clinical geneticists to establish a framework for understanding genetic mechanisms. We first present an overview of genomic structure ( Fig. 1.1 ), which begins with a description of the nuclear and mitochondrial genome. Using examples to help patients create a mental image of the human genome is helpful. For example, ask patients and their families to think of the human genome as books on a shelf ( Box 1.1 ). An understanding of how these function forms the basis for understanding the concepts of genetic counseling and prenatal testing (see Box 1.1 ).
Basic structure of the nuclear and mitochondrial genomes.
Box 1.1
Counseling Pearls
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Help patients create a mental image of their genome and weave the story around this picture.
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Visualize the genome as a set of books on a shelf (i.e., chromosomes), with each book containing the information that tells every cell of the body how to function. The sperm and egg each have 23 books before conception. After conception, each cell of the body has 46 books.
Types of Genetic Problems:
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Incorrect number of books (i.e., aneuploidy)—for example, Down syndrome (extra number 21 chromosome)
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One book stuck to another book (i.e., translocation)—for example, Robertsonian translocation
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Chapter or paragraph duplicated or deleted (i.e., microdeletion or duplication)—for example, DiGeorge syndrome (deletion of chromosome 22q11.2)
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Misspelled word (i.e., point mutation)—for example, delta F508 mutation that causes cystic fibrosis
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Genetic problems lead to an improper blueprint—cells perform their function improperly, resulting in birth defects, abnormal cell function, developmental delay, and so on
DNA Structure
Worldwide investment, interest, and contributions toward our understanding of the human genome created the need for a standardized nomenclature. Furthermore, reporting variants within the genome requires uniform reporting criteria. Understanding normal and abnormal inheritance patterns necessitates an understanding of DNA structure. The primary DNA structure is the nucleotide sequence. Single-stranded DNA consists of the nucleotides adenine (A), cytosine (C), guanine (G), and thymine (T), named by their respective nitrogen base (i.e., purine [A or C] and pyrimidine [G or T]) joined to a sugar (five carbon deoxyribose) with phosphate groups attached. The single-stranded nucleotide chain is held together by covalent phosphodiester bonds. When laboratories identify variation in primary structure (e.g., DNA sequence), reporting standards require the application of specific criteria to classify variants as pathogenic, likely pathogenic, benign, likely benign, or of uncertain significance. Secondary DNA structure describes how DNA strands join one another. Purines and pyrimidines join predictably (A to T and G to C) to form a double strand held together by weak hydrogen bonds (two for A to T and three for G to C). These strands can dissociate to allow recombination (normal human variation and disease). Abnormalities of recombination result in copy number variants (CNVs), also referred to as microdeletions and duplications . The five most common syndromes resulting from CNVs are (1) DiGeorge (22q11.2 deletion), (2) 1p36 deletion, (3) Prader-Willi (15q11.2-q13 paternal deletion), (4) Angelman (15q11.2-q3 maternal deletion), and (5) cri du chat (5p deletion). Tertiary structure is the orientation of DNA in space as a double helix, facilitated in part by histones. Histones are proteins that permit DNA to wind or unwind depending on their acetylated states. This function of histones changes the transcriptional activity of regions of the genome (epigenetics).
Cell Division
MEIOSIS
Gametes are derived from primordial germ cells specific to the ovary and testes. These primordial germ cells have 2n (46) chromosomes (diploid) but give rise to gametes, which have half that number, n (23) chromosomes (haploid). The process leading to this reduction division is termed meiosis . Meiosis is divided into meiosis I and II. One important distinction is that total DNA goes from 4n to 2n during meiosis I and 2n to n during meiosis II. The configuration of DNA (e.g., tetrad and sister chromatids) represented by chromosomes is also unique ( Table 1.1 ). There are characteristic phases (e.g., prophase, metaphase, anaphase, and telophase) within meiosis I and II. Prophase of meiosis I has five distinct stages (leptotene, zygotene, pachytene, diplotene, and diakinesis). During zygotene, homologous chromosomes (maternal and paternal chromosomes) align at the synaptonemal complex, giving way to a bivalent (two homologous chromosomes) tetrad (each chromosome has two sister chromatids). Homologous recombination occurs during pachytene, when sister chromatids of maternal and paternal homologs exchange segments of DNA, resulting in genetic variability among offspring from the same parents.
TABLE 1.1
Meiosis in the Developing Oocyte
| Stages/Phases | DNA | DNA Configuration | Comments | |
|---|---|---|---|---|
| Interphase (fetal life) | Three stages: G1, S, and G2 | 4n | Sister chromatids | Kinetochores hold sister chromatids at centromere S-phase content doubles (2n–4n) |
| Meiosis I | Prophase: Five stages: leptotene, zygotene, pachytene, diplotene, and diakinesis | 4n | Tetrads Chiasmata |
Nuclear membrane fragments DNA condensation begins Spindle develops Homologous chromosomes form a tetrad Chiasmata appear (regions of recombination between homologous chromosome) Crossing over between homologous pairs Stall during diplotene stage: 8 months’ gestation (primary oocyte) until puberty |
| Prometaphase | 4n | Tetrads Chiasmata |
Nuclear membrane is gone Spindle attached to shared kinetochore DNA is condensed Crossing over between homologous pairs |
|
| Metaphase | 4n | Tetrads Chiasmata |
Tetrads randomly align along metaphase plate Crossing over between homologous pairs |
|
| Anaphase | 4n | Sister chromatids | Homologs are pulled apart Sister chromatids remain together Random segregation toward opposite ends of cell |
|
| Telophase | 2n | Sister chromatids | Sister chromatids take a polar position Nuclear membrane starts to form Cell division begins |
|
| Cytokinesis | 2n | Sister chromatids | Nuclear membrane and cell division completed Stall: Until ovulation (secondary oocyte and first polar body) |
|
| Meiosis II | Prophase | 2n | Sister chromatids | Nuclear membrane fragments DNA condensation begins Spindle develops |
| Prometaphase | 2n | Sister chromatids | Nuclear membrane is gone Spindle attached to shared kinetochore DNA is condensed |
|
| Metaphase | 2n | Sister chromatids | Sister chromatids randomly align along metaphase plate Stall: Until fertilization |
|
| Anaphase | n | Chromosomes | Sister chromatids are pulled apart Random segregation toward opposite ends of cell |
|
| Telophase | n | Chromosomes | Chromosomes take a polar position Nuclear membrane starts to form Cell division begins |
|
| Cytokinesis | n | Chromosomes | Nuclear membrane and cell division completed Mature ovum and three polar bodies (first polar body also divides) |
In females, oogenesis begins in utero but stops during prophase I and is completely dormant by 8 months’ gestation (see Table 1.1 ). This arrested state occurs during the diplotene stage of prophase I. There are five stages of prophase I (leptotene, zygotene, pachytene, diplotene, and diakinesis). Recombination or “crossing over” occurs during these stages. A prolonged diplotene stage of prophase I ( known as dictyotene ) is seen only in oocyte development. In females, meiosis I resumes at puberty, and each month another one or more oocytes (a function of follicular recruitment) resumes to complete the reduction division (2n to n). Meiosis I is completed at the time of ovulation (first polar body is formed), and meiosis II begins, but is once again halted, this time during metaphase. Meiosis II is completed only if fertilization occurs (second polar body is formed). Fertilization most often takes place in the fallopian tube. An important distinction between male and female gamete development is the time in life at which meiosis is initiated and the time course to completion. In males, this is a short process (approximately 64 days), has its onset at puberty, and is continuous throughout a man’s reproductive life.
Mendel’s Laws
Mendel used pea plants and flowers as a model for his scientific observations, which remain relevant today. Among these observations are Mendel’s laws of inheritance ( Table 1.2 ), which provide a general description of how genetic variability is accomplished during meiosis. Although Mendel was unaware of recombination, the concept of gametes being uniquely different owing to chance is a tenet conveyed regularly in genetic counseling sessions.
TABLE 1.2
Mendel’s Laws of Inheritance
| Law | Principle | Clinical Pathology |
|---|---|---|
| Segregation | Alleles of the same gene segregate into separate gametes | Nonallelic homologous recombination (unequal crossing over) |
| Random assortment | Genes that yield distinct traits segregate independently when on separate chromosomes | Nonallelic homologous recombination (unequal crossing over) Aneuploidy rescue |
| Dominance | Some alleles are dominant, others are recessive, and dominant alleles will express | Point mutations (e.g., single-gene disorders) Microdeletions/microduplications (e.g., genes within a locus) Nonallelic homologous recombination Aneuploidy rescue |
Mitosis
Cellular DNA is located in the nucleus and mitochondria. Nuclear DNA within somatic cells is partitioned into 46 individual chromosomes, which defines a euploid cell (2n). Mitotic cell division ( Fig. 1.2 ) conserves this number as the zygote (fertilized egg) moves into embryonic and fetal stages of development.
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