Genomics Part 2

Incidence

Number of new disease cases in a defined population over a specific period; measures disease risk and whether disease frequency is changing over time.

Prevalence

Number of people affected by a disease in a specific population at a specific point, regardless of diagnosis time or disease duration; reflects disease burden.

What changes prevalence?

Duration of survival with disease, cure, and death can change prevalence.

Incidence and prevalence: shared use

Both can compare disease rates between populations, such as by sex, region, or racial/ethnic group.

Incidence and prevalence: key limitation

Neither explains why rates are changing or why they differ between groups.

Relative risk

Ratio of disease probability in a group with a specific risk factor to disease probability in a group without that factor.

Relative risk interpretation

Suggests whether a risk factor is associated with disease development, assuming the compared groups are otherwise similar.

Relative risk limitations

Shows correlation, not causation, and does not quantify an individual's absolute risk.

Polygenic trait

Results from the combined effects of multiple genes.

Multifactorial trait

Influenced by both genes and environmental factors.

Bell curve model

A normal distribution in which the most common combinations of influences form the peak and less likely combinations form the high and low outliers; used for quantitative traits such as height and baseline blood pressure.

Threshold model

Disease phenotype appears only when accumulated genetic and/or environmental liability exceeds a threshold.

Liability distribution

Bell-curve distribution of underlying disease influences; few risk factors place a person at the low-risk end, and accumulating factors raises risk toward the disease threshold.

Below versus above the liability threshold

Below the threshold, the person appears normal; above it, the disease phenotype is expressed.

Recurrence risk in polygenic or multifactorial disease

Generally higher when multiple close relatives are affected or disease is severe, and lower when only distant relatives are affected or disease is mild.

Monozygotic twins

Develop from one fertilized egg that splits and therefore have the same DNA.

Dizygotic twins

Develop when two eggs are fertilized by two sperm and therefore have different DNA.

Twin-study evidence for environmental influence

Differences in disease rate between genetically identical monozygotic twins suggest environmental effects.

Twin-study evidence for genetic influence

Similarity in disease rate between monozygotic twins suggests a strong genetic influence.

Adoption studies

Estimate genetic contribution by comparing disease in an adoptee whose biologic parent had the disease with controls lacking that family history.

Adoption-study evidence for genetic influence

A higher disease rate among children whose biologic parent had the disease suggests a genetic component.

Adoption-study limitation

Assumes the adoptive environment differs from the biologic parent's environment and that time with biologic parents was limited.

Polygenic risk score (PRS)

Numerical estimate of an individual's genetic predisposition to multifactorial disease based on their genetic markers and risk data from large genomic studies.

PRS interpretation

Expresses relative risk by comparing a person's genetic risk with that of people who have a different genetic makeup, usually along a low-to-high continuum.

Clinical value of separating genetic and environmental influences

Guides family-history assessment, genetic testing, modifiable-risk counseling, timing or aggressiveness of intervention, public-health efforts, and reassurance or destigmatization.

Epigenetics

Control of gene activity without changing the DNA sequence.

Overall effect of epigenetic change

Turns genes on or off, changing protein synthesis and ultimately phenotype; changes may be physiologic, environmentally induced, disease-causing, reversible, inherited by daughter cells, or sometimes transmitted through gametes.

DNA methylation

Attachment of methyl groups (-CH3) to DNA, blocking transcription factors and silencing genes by reducing or eliminating protein expression.

DNA methylation examples

X-inactivation turns off one X allele in XX people; excess or aberrant methylation can reduce tumor-suppressor expression, such as BRCA1, and contribute to cancer.

Hydroxymethylation

Attachment of a hydroxymethyl group to DNA that promotes demethylation and turns back on genes silenced by methylation.

Hydroxymethylation significance

Can normally counterbalance methylation; abnormally low levels are associated with neural-tube defects and hematologic malignancies.

Histone modification

Chemical changes to histone proteins alter how tightly DNA is wrapped and thereby alter gene expression.

Tightly wrapped DNA

Inaccessible to transcription factors and therefore turned off.

Histone modification in differentiation

Keeps unneeded chromatin sections tightly wrapped during normal cell specialization.

Noncoding RNAs

Can regulate methylation and histone modification, bind or modulate mRNA to alter translation, or bind ribosomes and block translation.

Epigenetics in embryonic development

Extensive methylation of specific DNA sequences drives differentiation by leaving active only the genes required for each cell type.

Embryonic stem cells

Totipotent cells capable of developing into any somatic cell type.

Housekeeping genes

Genes required for function and maintenance of all cells; they are not methylated and remain transcriptionally active in all cells.

Genomic imprinting

Predictable methylation and silencing of one parental allele in a small subset of genes; the maternal or paternal copy is always inactive.

Why parent of origin matters in genomic imprinting

If a mutation or deletion affects the normally active parental copy, no functional allele remains, so the same chromosomal deletion can produce different phenotypes depending on which parent transmitted it.

Prader-Willi and Angelman syndromes: shared genetic change

Both can result from the same deletion of about 4 million base pairs on the long arm of chromosome 15, encompassing both disease regions.

Prader-Willi syndrome inheritance

Deletion of the paternal allele removes the active PWS region because the maternal PWS region is normally inactive.

Prader-Willi syndrome phenotype

Mild-to-moderate intellectual disability, short stature, and constant hunger.

Angelman syndrome inheritance

Deletion of the maternal allele removes the active AS region because the paternal AS region is normally inactive.

Angelman syndrome phenotype

Severe intellectual disability, seizures, and an ataxic gait.

Epigenetics and aging

Epigenetic modifications accumulate across the lifespan; older monozygotic twins show increasing methylation and phenotypic differences, especially with major lifestyle differences such as smoking.

Cancer: decreased DNA methylation

Can increase oncogene activity and is seen as benign neoplasms progress to malignancy.

Cancer: tumor-suppressor hypermethylation

Decreases tumor-suppressor transcription; examples include RB1 in retinoblastoma and BRCA1 in breast cancer.

Epigenetic cancer therapy rationale

Because epigenetic modifications can be reversed, demethylating agents can be used in some hematologic malignancies.