Genetics is the science of heredity and inherited variation. It considers the biological

information all living organisms require to grow, develop, reproduce, and die. It considers, as

well, how traits are transmitted from one generation to the next. The chemical nature of this

information is the same in organisms as simple as microbes and as complex as man.

All organisms package their genetic or genomic information in tiny cellular structures called

chromosomes. The relationship between the words genome, chromosome, and gene may be

thought of as a set of Russian dolls: a genome is composed of a set of chromosomes; a chromosome is composed of a set of genes; a gene is composed of a set of nucleic acids. In humans, and other eukaryotes (organisms composed of one or more cells containing a visible nucleus and organelles) which reproduce sexually, chromosomes are paired, one inherited from each parent. Human cells contain 23 pairs of chromosomes, for a total of 46. These diploid cells that contain two copies of every chromosome transmit their chromosomes during two kinds of cell division: mitosis and meiosis. In mitotic cell division, which occurs in all cells of the body, each “daughter cell” receives the identical chromosome complement of its parent cell. In meiosis, which occurs only in germ cells (reproductive cells), the diploid number (46) is halved, producing haploid gametes (cells that will fuse during fertilization), each with 23 chromosomes. Inherited variation between any two people is largely a function of two events that occur during meiosis: random chromosome separation and crossing over between members of each chromosome pair. Reproduction proceeds through the union of gametes, an oocyte (egg) from the female and a sperm from the male. The fertilized egg, or zygote, is diploid, as are all other body cells. Prenatal and postnatal development occurs through mitosis, which is how the single-cell zygote develops into a 40-billion cell newborn and a 100-trillion-cell adult.

Traits are transmitted from one generation to the next by genes. The Austrian monk, Gregor

Mendel, discovered the basic rules of this transmission that is, gene segregation and

assortment in the mid-nineteenth century by studying pea plants. Trait transmission in

human pedigrees follows the same rules. Traits attributable to single genes (referred to as

“Mendelian traits”) are inherited as dominants or recessives. They may be autosomal or

sex-linked. Traits attributable to multiple genes and those demonstrating imprinting or

maternal inheritance display more complex patterns.

Genes are the units of inheritance. They are composed of DNA (deoxyribonucleic acid). Genes store information in linear DNA molecules composed of a four-letter chemical alphabet—composed of the bases G (guanine), C (cytosine), A (adenine), and T (thymine), which form the unique part of nucleotides, and which give each gene its unique function. Each gene has a unique sequence of these nucleotides, which, in turn, underlies its unique function. The DNA molecule is a double strand of nucleotides carrying complementary G-C or A-T base pairs. The complementarity of double-stranded DNA is the key to understanding how DNA functions in inheritance.

Within the cells of an organism, DNA molecules carrying genes are assembled into chromosomes: organelles composed of DNA and associated proteins. The sum total of genes and chromosomes in each cell is its genome. The nuclear human genome consists of 24 distinct kinds of chromosomes, composed of 6 billion nucleotides and about 21,000 genes. Only about 2% of the DNA in the human genome is composed of genes that encode proteins. The remainder is comprised of nucleotide sequences with variably understood regulatory and evolutionary significance.

Genomics, the study of whole genomes, was made possible by determining the complete DNA sequence of humans and that of about 400 other organisms. This triumph of modern genetics, facilitated by employing old technologies (such as gene cloning, restriction mapping, and gel electrophoresis) and new ones (such as high throughput DNA sequencers and power computational tools)—is beginning to reveal the kinds and extent of variation in DNA structure not previously anticipated and not yet well understood. Already, however, the study of remarkably common single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) is providing us with information about mechanisms of susceptibility to many human traits and disorders.

The central dogma of gene action is abbreviated: DNA/RNA/Protein. Genes transmit their

information by being transcribed, i.e., their DNA codes for a complementary RNA referred to

as messenger RNA (mRNA). In turn, mRNAs are edited, leave the nucleus, and are translated

into proteins the molecules largely responsible for the functions cells carry out. Translation

occurs according to a universal genetic code: the sequence of nucleotides in mRNA, read as

triplets (called codons) that specify the sequence of amino acids in proteins. This fundamental pathway of gene expression is modulated such that only a subset of genes is active in any one tissue thereby explaining differentiation, that is, the structural and functional differences between, for example, a brain cell and a heart cell. Gene expression may be modified in a number of ways: by changes in DNA primary structure such as mutations; by chemical (epigenetic) modification of DNA; and by interference with mRNA structure or function produced by small RNA species, called siRNAs and miRNAs.

A mutation is a heritable change in the nucleotide sequence or arrangement of DNA. In the

positive, evolutionary sense, mutations are responsible for the selective advantage that one

species gain over another. In the negative sense, mutations cause or increase susceptibility to thousands of human disorders. Mutations can occur at three different levels: genome, chromosome, and gene. Genome mutations result from missegregation (failure of chromosomes to properly segregate) during meiosis and produce changes in chromosome number. Chromosome mutations are caused by rearrangements in the structure of a chromosome, such as translocations or deletions. Gene mutations alter the base sequence of a gene. Mutations occur in germ cells, somatic cells, and mitochondria. Germ-line mutations affect DNA in all cells and are transmitted to offspring. Mitochondrial mutations affect mitochondrial DNA, all of which is inherited from the mother’s egg; accordingly, they are inherited maternally. Somatic mutations affect cells in a single tissue and are not transmitted to the next generation. Mutations act, generally, by perturbing the function of proteins and regulatory processes, and they may do so from the earliest to the latest stages of life.

DNA is not static. Rather, its sequence changes at a slow but measurable rate all the time.

Mutations are of central importance to all life forms, including humans. Without mutations,

our species would not have evolved over several billion years. Without mutations, individuals

would not differ from one another, even within the spectrum that is considered “normal.”

Without mutations, humankind also would not be faced with a myriad of spontaneous abortions, inherited disorders, or cancers. Therefore, we must comprehend both the nature of mutations and the effects they produce

Biological evolution is the central organizing principle of modern biology and has revolutionized our understanding of life on Earth. It has provided a scientific explanation for why there are so many different kinds of organisms on our planet and how all these organisms became part of a continuous lineage—including humans. DNA is central to understanding biological evolution because all traits in virtually all organisms originate from DNA and are transmitted from generation to generation through it. New mutations in DNA result in the variation of traits that enable the organism to adapt more successfully to its environment. Through increased reproductive fitness, such traits will increase in frequency in a population from one generation to the next, as will the frequency of the DNA changes responsible for them. The process by which genotypes best suited to survive and reproduce in a given environment, and so gradually increase the overall ability of the population to thrive, is called natural selection.

Each human being has his or her unique genome. This includes monozygotic twins whose

DNA sequences are identical but whose packaging of DNA differs slightly. This genetic

uniqueness expresses itself in the form of physical, chemical, and behavioral individuality. In

the past, an understanding of this individuality was barely hinted at by the existence of rare,

single-gene disorders and by estimating the frequency of polymorphic protein variants in

a population of healthy people. As we enter the genomic era, genome-wide studies, including complete DNA sequences on a small but increasing number of people, have already attested to considerable differences in single nucleotide polymorphisms (SNPs), small insertions and deletions, copy number variations (CNVs), and in heterozygosity for rare disease genes. As such studies are conducted on more individuals and groups, they will lead to greater understanding of normal traits and common disorders. Ultimately, this will get us closer to finding out how each of us differs genetically from anyone else.

The 46 chromosomes found in the nucleus of humans cellsd22 pairs of autosomes and one

pair of sex chromosomes are best examined during mitotic metaphase. Metaphase chromosomes can be visualized under a microscope by staining them with various dyes. Even more definitive identification employs fluorescence in situ hybridization (FISH). Chromosomes may be examined in situ using light microscopy on intact cells. More often, a karyotype prepared by cutting out and mounting individual chromosomes from a metaphase spread is studied. In a typical karyotype, chromosomes are displayed in homologous pairs according to size and to the position of the centromere.

Abnormalities in chromosome number (aneuploidy) or structure are found in 0.7% of

newborns, but this figure is a gross underestimate of the significance of such abnormalities to human health: approximately 75% of all human conceptuses are aborted spontaneously due to such chromosomal defects. Cytogenetic testing (the study of chromosomes) is indicated under the following circumstances:

1. advanced maternal age

2. previous infertility

3. still births

4. neonatal deaths

5. birth defects

6. chromosome abnormalities in first-degree relatives

Most kinds of aneuploidy—polyploidy (extra sets of all chromosomes), trisomy (extra copy of

one chromosome), or monosomy (loss of a single chromosome)—are found in aborted

fetuses. Those aneuploid states compatible with full-term gestation include: trisomy for

chromosomes 13, 18, and 21; different sex chromosome trisomies (XXX, XXY, XYY) and

quadrisomies (XXXX; XXYY); and monosomy for the X chromosome. A variety of structural

rearrangements are also observed cytogenetically. These include insertions, deletions, inversions, and translocations. The clinical consequences of such aneuploidies or structural

rearrangements, most of which result from non-disjunction or chromosome instability

occurring during meiosis, depend on several factors:

1. which chromosome (or chromosomes) is involved

2. which genes have been perturbed

3. how much chromosomal material has been added or subtracted

4. what compensatory mechanisms exist (such as X chromosome inactivation)

5. whether genomic imprinting is involved

Mutations of single genes have been documented at more than 10% of the estimated 21,000 genetic loci in the human genome that code for proteins. These single-gene mutations have a considerable effect on child health: they occur in 0.4% of newborns; they are responsible for 5% of hospitalizations; and they cause 8% of deaths. The study of these disorders—once called “inborn errors of metabolism” and now generally referred to as “inherited metabolic diseases”—has been of value in several ways: by elucidating normal biochemical pathways of anabolism and catabolism; by defining the biochemical mechanisms of myriad disorders and the nature of the gene mutations that cause them; and by using this information to develop diagnostic tests and therapeutic strategies.

This value has been extracted by studying disorders caused by single mutations at four logically constructed, ascending levels: the clinical phenotype; the metabolic pathway or specific reaction; the protein affected; and the genetic locus perturbed. Although each disorder is unique, reflecting as it does the locus and its product, some generalities deserve mentioning:

1. Most disorders are genetically heterogeneous, that is, each results from a wide variety of different mutations (missense, nonsense, frameshift, and splicing) which interfere with the function of a single protein. A few are caused by trinucleotide repeats

2. They reflect modification of the structure and function of one or more of the kinds of proteins found in the human body: enzymatic, structural, regulatory, circulating, and membrane. Organ dysfunction follows from differential gene expression

3. Some are inherited as dominant traits, others as recessives; some are autosomal, others sex-linked

4. Some, like red hair, are benign traits; others are uniformly fatal during childhood. Still others are compatible with extended life but impair organ function in serious ways

5. Whereas some conditions are found with near equal prevalence in all ethnic groups, most show ethnic clustering

Most common human phenotypes reflect interactions between genes and the environment and are termed “multifactorial.” Some multifactorial phenotypes are ubiquitous physiologic traits such as height, weight, and mathematical aptitude. Others are a multitude of common disorders encountered at birth (cleft lip, neural tube defects), in children (asthma, juvenile diabetes mellitus), or in adults (high blood pressure, coronary artery disease, schizophrenia). A small number, like eye color and finger-tip ridge count, are called polygenic traits because they result from the action of two or more genes with little or no environmental contribution.

Multifactorial traits run in families, but not according to Mendelian modes of inheritance. Some, like height, are quantitative traits in that they vary continuously over a range of measurement and display a normal (Gaussian) distribution curve. Others, such as cleft lip or schizophrenia, are qualitative traits with two classes of people—affected or unaffected, although even in affected individuals there may be a range of phenotypes. A variety of mathematical tools are employed to determine that genes play a part in quantitative or qualitative multifactorial conditions and to estimate the magnitude of that genetic contribution. These tools include empiric study, intrafamilial correlation, and twin concordance.

Identifying the particular genes involved and determining how they interact with one another and with the environment has proven to be much more difficult. Although there is not a single instance in which complete understanding of a multifactorial trait’s biological basis has been produced, progress is being made. Such progress uses candidate gene studies (seeking mutations in genes whose function is relevant to the trait), linkage analysis (examining

pedigrees for linkage between the trait and one or more genetic markers), and genome-wide association studies (in which the frequency of single nucleotide polymorphisms is compared

in controls and those with a particular trait or disorder). As complete genome sequencing becomes technically feasible and financially affordable, more comprehensive understanding is expected.

The human genome has, until very recently, been thought of in classical terms

1. Chromosomes and genes occur in pairs—one from each parent

2. A pair of alleles at each locus produces dominant, recessive, and sex-linked traits

3. Mutations produce heritable changes in DNA that often have deleterious results

The Human Genome Project has taught us, however, that these classic understandings are over-simplified and incomplete: the function of chromosomal DNA is sometimes affected by epigenetic chemical modification; some genes are duplicated and others have multiple alleles; some Mendelian disorders result from mutations at two different loci, or even three. From these observations has come the current view of the genome:

1. that only 2% of it codes for proteins

2. that about half is present in single copy sequences

3. that almost half of it consists of a variety of repeating sequences

4. that variation in copy number affects 10-20% of the genome

It is already safe to conclude that the human genome is dynamic—not fixed; that it is capable of great variability which is occurring continually. Although any two humans are 99.6% identical in genomic DNA sequence, the other 0.4% of non-identity is already beginning to provide a glimpse of what makes each human genetically unique.

Birth defects occur in 5-7% of newborns. About half of these defects affect major organs, including the brain, heart, and limbs; the remainder are minor (crooked fifth finger, missing fingernails, etc). These birth defects reflect but a small minority of the lethal embryonic errors that occur during human gestation and which end in spontaneous abortion. Five critical cellular events must occur during successful embryonic and fetal development: proliferation,

differentiation, migration, communication, and apoptosis. These events—some sequential, some concurrent, all critically timeddtake place during the embryonic (weeks 1-8) and fetal (weeks 9-38) periods of gestation

This program is controlled by a series of genes acting at precise intervals in precise fashion. Some of these genes (maternal-effect) are encoded by the mother’s genome and synthesize products transferred, first, to the oocyte, and then to the zygote and early embryo. The remainder of the genes controlling development are the embryo’s own, and they control such critical processes as:

1. segmentation (dividing the embryo into parts from head to tail)

2. pattern formation (fate of cells in each segment)

3. cell signaling (chemical communication between an within cells

4. apoptosis (programmed cell death essential for tissue remodeling)

When this developmental program works perfectly, a single-cell zygote ultimately becomes a 40-billion cell neonate. But a myriad of accidents lead to the birth of children with defects. Each of the three major classes of genetic disorders (chromosomal, single gene, and multifactorial) underlies a fraction of birth defects. The nature, severity, and outcome of any particular defect depend on what part of the genome is affected and to what degree.

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Population genetics is the quantitative study of the distribution of genetic variation in a population and of how the frequencies of its genotypes, alleles, and phenotypes are maintained or changed. It seeks answers to such practical questions as why the frequency of

phenylketonuria (PKU) in Caucasians is so much greater than in Japanese, or why the frequency of the sickle cell allele varies markedly in people from different West African countries. The mathematical cornerstone of population genetics is the Hardy-Weinberg law or principle. The law has two parts. First, it states that in a large, randomly mating population with two alleles at a locus (for example, A and a), there is a simple relationship between these

allele frequencies (frequency of A ¼ p; frequency of a ¼ q) and the genotype frequencies (p^2, 2pq, or q^2) they define. Second, it holds that this relationship between allele and genotype frequencies, constructed simply on the binomial expansion of (p + q)^2, does not change from one generation to the next. When a population conforms to this two-part law, it is in Hardy-Weinberg equilibrium. In such populations, the law is of great value in showing why dominant traits do not increase in frequency from one generation to the next and why recessive traits do not decrease. Further, the law is regularly used in genetic counseling settings

where estimates of genotype, allele, and carrier frequencies are calculated from limited phenotypic information in small families, such estimates then being employed to estimate specific genetic risk.

Hardy-Weinberg equilibrium is never fully realized in human populations because it is perturbed by one or more deviations. First, individuals do not usually mate randomly. Mating is more often assortative (mate choice depends on geographic proximity), stratified (within an ethnic subset), or inbred (among relatives or a small group). Second, allele frequencies do not remain constant for a number of reasons: random or chance events producing major

changes in population size and composition (called “genetic drift”); migration of individuals from one population to another, followed by mating between the populations, referred to as gene migration; new mutations that occur at a low rate constantly; and natural selection in which some genotypes are better suited to reproduce and thrive (called “fitness”) and therefore give rise to a disproportionate share of offspring. A particular form of such selective advantage occurs when gene-environment interaction leads to the situation in which the fitness of heterozygotes for a particular genetic condition exceeds that in either homozygote. This is referred to as heterozygote advantage, and has been best studied in the relationship between sickle cell anemia and malaria.

Such examination of single-gene frequencies and perturbations is now being complemented and supplemented by genome-wide studies employing SNPs and CNVs. These genomic approaches have revealed that most genetic variation occurs within a population rather than between two populations—adding additional complexity to the meaning of the word “race” and making it clear that such population categories as European, Asian, African, and Hispanic, while distinct in terms of their geographic origins, are in no way distinct genetically.

As we understand more about the structure of genes and genomes, that information informs our ideas about the evolution of populations. Molecular evolution is concerned with determining how the study of genomes, chromosomes, genes, and proteins helps us account for the evolution of our species—and other species as well. The study of molecular evolution employs

many techniques (DNA hybridization, chromosome banding, amino acid sequences in proteins, and whole-genome sequencing), all aimed at providing more precise estimates of the timing of evolutionary events (molecular clocks), and of the relationship between our species and that of others near or distant from our own (ancient DNA).