Genomics Part 1

Genetics

Study of individual genes and their role in inheritance, including standard inheritance mechanisms and disorders tied to specific genes or genetic patterns.

Genomics

Study of all of a person's genes (the genome), including gene-gene interactions, genome-environment interactions, and diseases involving multiple genes.

Genomic medicine

Use of a person's genomic information in clinical care to support earlier diagnosis, outcome prediction, and individualized treatment.

Gene

Basic unit of inheritance composed of DNA sequence(s) on a chromosome; genes typically code for specific proteins or protein segments.

Locus

The position of a gene on a chromosome.

Alleles

Different forms of the same gene with small differences in DNA sequence that contribute to differences in phenotype.

DNA nucleotide components

One deoxyribose molecule, one phosphate group, and one nitrogenous base: adenine, cytosine, thymine, or guanine.

DNA double helix

Two nucleotide strands held together by weak hydrogen bonds; these bonds can be broken to allow DNA replication.

Codon

A group of three nucleotides that encodes a specific amino acid.

Stop (nonsense) codons

Three codons that signal the end of a gene and terminate translation.

Redundancy of the genetic code

Multiple codons can correspond to the same amino acid; there are 64 potential codons but only 20 amino acids.

Universality of the genetic code

The vast majority of organisms use the same DNA codons to specify proteins; human mitochondrial DNA is an important exception.

Mitochondrial DNA

Extranuclear DNA that encodes essential genes for mitochondrial function, uses some codons differently than nuclear DNA, and is inherited only from the mother.

DNA replication

Part of normal cell replication (mitosis) that produces two new DNA helices from one helix through unwinding, stabilization, replication, and proofreading.

DNA polymerase

Key replication enzyme that adds complementary nucleotides to a single-strand template and proofreads by detecting, excising, and replacing incorrect nucleotides.

Leading strand replication

Continuous DNA replication.

Lagging strand replication

Replication occurs in reverse, requires an RNA primer, and proceeds in sections.

Telomeres in replication

Non-protein-coding DNA that provides a cushion to compensate for the lack of space for a primer to bind.

Mutation

Any inherited alteration of genetic material, commonly but not exclusively caused by replication errors.

Missense mutation

Substitution of one base for another that changes a codon and may change the amino acid sequence.

Silent mutation

A base substitution with no effect on the amino acid because the genetic code is redundant.

Nonsense mutation

A base-pair substitution that generates a stop codon, causing premature termination of translation and protein synthesis.

Frameshift mutation

Insertion or deletion of a number of bases not divisible by three; alters the reading frame and all codons downstream.

Mutagen

An exogenous chemical or physical agent that increases mutation rate; examples include ionizing or UV radiation and certain chemicals.

Mutation hot spot

A DNA sequence with a particularly high mutation rate during replication or repair; may be location-driven or sequence-driven, such as CG sequences.

Transcription

Formation of an mRNA copy from a specific gene's DNA sequence in the nucleus by RNA polymerase; the processed mRNA then moves to the cytoplasm.

RNA versus DNA

RNA uses uracil instead of thymine and ribose instead of deoxyribose.

Translation

Protein synthesis from an mRNA template at ribosomes in the cytoplasm or on the endoplasmic reticulum.

tRNA in translation

Brings specific amino acids to the ribosome in the sequence dictated by mRNA.

Completion of translation

A ribosomal enzyme forms peptide bonds until the ribosome reaches a termination signal on mRNA.

Genotype

The DNA-sequence composition of a given gene.

Phenotype

An individual's observable traits, determined by genotype and environmental factors.

Gametes

Reproductive cells (sperm and ova) that are haploid, contain 23 total chromosomes, and form by meiosis.

Somatic cells

All body cells other than gametes; they are diploid, contain 23 chromosome pairs (46 total), and form by mitosis.

Euploid

Having the expected chromosome number: 46 chromosomes (2n) in human somatic cells or 23 chromosomes (1n) in human gametes.

Autosomes

The 22 chromosome pairs whose members are virtually identical in DNA sequence and are responsible for most body functions.

Sex chromosomes

The 23rd chromosome pair, typically XX (homologous; genetic female) or XY (nonhomologous; genetic male).

Karyotype

Visualization of all chromosomes during metaphase; staining reveals bands, and notation states chromosome count and sex pattern, such as 46,XX or 46,XY.

Numerical chromosome abnormalities

A larger or smaller chromosome number than expected; may affect complete sets (polyploidy) or specific chromosomes (aneuploidy).

Clinical impact of numerical chromosome abnormalities

Common in conceptions, present in about half of first-trimester spontaneous abortions, and a notable cause of intellectual disability in live births.

Polyploidy

Addition of one or more complete chromosome sets to the genome.

Triploidy and tetraploidy

Three copies of every chromosome (3n; e.g., 69,XXX) or four copies (4n; e.g., 92,XXXX); nearly all affected fetuses are spontaneously aborted or stillborn.

Somatic polyploidy

Normal acquisition of extra chromosome sets in some liver cells, cardiac myocytes, and epithelial cells; may increase cell size and support specialized function.

Aneuploidy

Loss or gain of a chromosome copy, usually involving one specific chromosome.

Nondisjunction

Failure of homologous chromosomes in meiosis I or sister chromatids in meiosis II to separate appropriately, producing gametes with two or no chromatids.

Major nondisjunction risk factor

Older maternal ovum age increases the risk.

Trisomy

An aneuploid cell has three copies of one chromosome.

Monosomy

An aneuploid diploid cell has only one copy of a chromosome; autosomal monosomy is lethal in utero.

Why sex-chromosome aneuploidy is generally less severe

Only one X is usually active per cell, at least one X is required for survival, and the Y chromosome contains limited genetic material.

Survivable autosomal trisomies

Trisomies 13, 18, and 21 can survive to birth but cause developmental abnormalities; other complete autosomal trisomies do not survive to term.

Partial trisomy

Only a segment of a chromosome is present in triplicate and generally has less clinical impact than complete trisomy.

Mosaic trisomy

Only some cells have three copies of a chromosome while others have two; mosaicism means two or more cell lines with different karyotypes.

Trisomy 21 (Down syndrome)

Most common chromosomal disorder; findings can include intellectual disability, upward-slanting eyes, flattened nasal bridge, short neck, palmar crease, hypotonia, short stature, congenital heart defects, leukemia risk, and early-onset dementia risk.

Trisomy X

47,XXX; phenotypically female, usually without overt physical abnormalities, but may have infertility, menstrual irregularity, or learning disabilities.

Turner syndrome

45,X; phenotypically female with abnormal ovarian/internal genital development, low estrogen, absent menarche and secondary sex characteristics, short stature, and a webbed neck.

Klinefelter syndrome

Usually 47,XXY; phenotypically male with gonadal failure and infertility, reduced testosterone, gynecomastia, reduced body hair, and vocal alterations.

Structural chromosome abnormalities

Result when chromosome breakage is not repaired or is repaired abnormally, or when errors occur during normal exchange of DNA between homologous chromosomes in meiosis.

Clastogens

Agents that increase chromosome-breakage risk, including ionizing radiation, some viral infections, arsenic, and benzene.

Chromosomal deletion

Loss of a chromosome portion during repair or unequal crossover; usually clinically significant. Cri du Chat results from deletion of part of chromosome 5's short arm.

Chromosomal duplication

Repetition of a chromosome portion, usually due to a repair error; impact depends on magnitude and location.

Chromosomal inversion

A chromosome portion breaks off and reattaches upside down; no net genetic material is gained or lost, but offspring may develop duplications or deletions during gamete formation.

Translocation

Transfer of a chromosome portion to a nonhomologous chromosome.

Reciprocal translocation

Breaks in two different chromosomes followed by exchange of genetic material.

Philadelphia chromosome

Reciprocal translocation between chromosomes 9 and 22 that produces an altered chromosome 22 and is associated with CML.

Robertsonian translocation

Fusion of the long arms of two nonhomologous chromosomes at the centromere, with loss of nonessential short-arm DNA; carriers have 45 chromosomes and risk numerical abnormalities in offspring.

Why a balanced translocation can affect offspring

A carrier may produce an unbalanced gamete with one normal chromatid and one translocated chromatid, causing excess of one chromosome's DNA and loss of another's.

Fragile site

A chromosome region prone to a characteristic break or constriction, sometimes due to unreplicated DNA or excess repeated codons.

Fragile X syndrome

Caused by 200 or more repeated CGG codons on the X chromosome; causes intellectual disability and tends to produce a more severe phenotype in males.

Mendelian trait

A trait attributed to a single gene.

Homozygous alleles

The two alleles in a gene pair are identical.

Heterozygous alleles

The two alleles in a gene pair are not identical.

Dominant allele

Allele whose observable effect appears in a heterozygote; typically represented by a capital letter.

Recessive allele

Allele masked in a heterozygote; its effect appears when the recessive allele is homozygous.

Carrier

A heterozygous person with one disease-causing recessive allele who does not exhibit the recessive disease.

Codominance

Both alleles contribute to the observable phenotype, as in AB blood type.

Autosomal dominant inheritance

One disease-causing allele produces disease; males and females are equally affected and transmit it equally, generations are generally not skipped, and an affected heterozygous parent with a normal partner gives each child a 50% recurrence risk.

Two heterozygous parents with an autosomal dominant disease

Each child has a 75% chance of inheriting the disease genotype.

Homozygous parent with an autosomal dominant disease

Can pass only a disease-causing allele, so inheritance risk is 100% regardless of the partner's genotype.

Recurrence risk versus observed family outcome

A 50% recurrence risk applies independently to each child; chance can result in all or none of one family's children being affected.

De novo mutation

Spontaneous mutation in a specific parental germ cell; can cause disease without family history, gives siblings low recurrence risk, but can be passed by the affected person according to the usual inheritance pattern.

Autosomal recessive inheritance

Disease requires two disease-causing alleles; males and females are equally affected, disease may skip generations, and affected siblings may have unaffected carrier parents.

Carrier × normal parent in autosomal recessive inheritance

No children are expected to have disease; each child has a 50% chance of being a carrier.

Carrier × carrier in autosomal recessive inheritance

Each child has a 25% disease risk, 50% carrier probability, and 25% probability of two normal alleles.

Autosomal recessive disease risk factors

More likely in populations with limited genetic variation or consanguinity.

X-linked recessive inheritance

Disease is more common in males because they lack a second normal X allele; examples include hemophilia A, hemophilia B, and G6PD deficiency.

Affected father in X-linked recessive inheritance

Passes the disease-causing X to all daughters (who become carriers) and to no sons.

Carrier mother in X-linked recessive inheritance

Passes the disease allele to 50% of offspring: 50% of sons are affected and 50% of daughters are carriers.

X-inactivation

Permanent inactivation of one X chromosome in female somatic cells during the first 7-14 days of embryonic development, preventing excess X-linked gene products.

Barr body

The highly condensed, inactivated X chromosome; normally present in female cells and absent in male cells.

Female X-chromosome mosaicism

The maternal or paternal X is randomly inactivated in each early embryonic cell, and that same X remains inactive in all descendants of that cell.

Penetrance

Percentage of people with a specific genotype who also exhibit the expected phenotype.

Incomplete penetrance

Some people with a disease-causing genotype never show the phenotype but can still transmit the allele; penetrance may increase with age.

Expressivity

Variation in phenotype or disease severity among people with the same genotype due to other genes, environmental factors, or mutation type.

Penetrance versus expressivity

Penetrance asks whether the expected phenotype appears at all; expressivity asks how the phenotype varies in severity or form when it appears.