Fundamentals of Genetics and Inheritance Patterns

DNA Structure

DNA is a double helix composed of nucleotides, each containing a phosphate group, a deoxyribose sugar, and one of four nitrogenous bases (adenine, thymine, cytosine, guanine).

Purines

Two-ringed nitrogenous bases, including Adenine (A) and Guanine (G), found in both DNA and RNA.

Pyrimidines

Single-ringed nitrogenous bases, including Cytosine (C), Thymine (T), and Uracil (U), with specific pairing rules.

Adenine-Thymine Pairing

Adenine pairs with Thymine (T) in DNA through 2 hydrogen bonds.

Adenine-Uracil Pairing

Adenine pairs with Uracil (U) in RNA through 2 hydrogen bonds.

Cytosine-Guanine Pairing

Cytosine pairs with Guanine (G) in both DNA and RNA through 3 hydrogen bonds.

Function of DNA

DNA stores and transmits genetic information, with genes encoding instructions for building proteins.

Genetic Variants

Differences in the DNA sequence, which can be single nucleotide polymorphisms (SNPs), insertions, deletions, or copy number variations.

Mitosis

A process through which a single cell divides to produce two genetically identical daughter cells, key for growth, repair, and asexual reproduction.

Meiosis

A specialized form of cell division in gametes that results in four genetically distinct cells with half the number of chromosomes.

Crossing Over

Occurs during Prophase I of meiosis when homologous chromosomes exchange genetic material at chiasmata.

Independent Assortment

Happens during Metaphase I when homologous chromosome pairs align randomly, allowing for over 8 million possible chromosome combinations in humans.

Linkage Disequilibrium (LD)

Describes the non-random association of alleles at two or more loci, important for mapping genetic diseases.

Population Stratification

Differences in allele frequencies between subpopulations due to distinct ancestry or evolutionary histories.

Family Genotype Prediction

Using Mendelian inheritance rules to predict possible genotypes and phenotypes in family members.

Odds Ratio (OR)

An OR greater than 1 indicates a positive association between exposure (or genotype) and disease, while an OR less than 1 suggests a protective association.

Allele Count

For each genotype, count the number of copies of the allele in question.

Allele A count

Count of allele A calculated as (10 x 2) + (20 x 1) = 40

Allele Frequency

Frequency (p) calculated as 40 / (2*40) = 0.5

Pharmacogenetics

Focuses on how variations in a single gene influence an individual's response to drugs.

Pharmacogenomics

Studies how the entire genome affects drug response, aiming to tailor drug therapy based on a patient's genetic makeup.

Ultra-Rapid Metabolizers

Process drugs extremely fast, often leading to reduced drug effectiveness because the medication is broken down too quickly.

Normal (Extensive) Metabolizers

Metabolize drugs at an expected rate, meaning standard dosages typically work as intended.

Intermediate Metabolizers

Have a slower metabolism than normal metabolizers, which may require dosage adjustments for optimal drug response.

Poor Metabolizers

Process drugs very slowly, increasing the risk of drug accumulation and potential toxicity.

Applications in Medicine

These fields contribute to personalized medicine, with variants in enzymes like CYP450 altering drug metabolism.

Hardy-Weinberg Equilibrium (HWE)

A principle stating that allele and genotype frequencies in a population remain constant from generation to generation in the absence of evolutionary influences.

HWE Conditions

1. No mutations, 2. Random mating, 3. No natural selection, 4. Large population size, 5. No gene flow.

ABO Blood Types

The ABO blood system is controlled by a single gene with three alleles: (I^A), (I^B), and (i).

Blood Type A

Genotypes: (I^A I^A) or (I^A i)

Blood Type B

Genotypes: (I^B I^B) or (I^B i)

Blood Type AB

Genotype: (I^A I^B) (codominance, where both antigens are expressed)

Blood Type O

Genotype: (ii) (lack of A or B antigens)

Inheritance Patterns

The inheritance of ABO blood types can be predicted using Punnett squares based on the dominant and co-dominant relationships among the alleles.

Autosomal Dominant (AD)

A single copy of the dominant allele will result in the phenotype; Example: Huntington's disease.

Autosomal Recessive (AR)

Two copies of the recessive allele are needed to express the trait; carriers are usually asymptomatic; Example: Cystic fibrosis.

X-Linked Dominant

A dominant trait located on the X chromosome; often, heterozygous females show the phenotype while affected males may be more severely impacted.

X-Linked Recessive

More commonly affects males since they have one X chromosome; females are usually carriers unless they have two copies of the recessive allele; Example: Hemophilia A.

Punnett Squares

Tools that help to visualize and calculate the probability of inheriting traits based on parental genotypes.

Pedigree Analysis

Used to track inheritance patterns through family generations to determine carriers and affected individuals.

Point Mutations

A single nucleotide change (e.g., missense or nonsense mutations).

Insertions/Deletions

Can cause frameshift mutations altering the reading frame of genes.

Copy Number Variations (CNVs)

Duplications or deletions that affect the number of copies of a gene.

Single Nucleotide Polymorphisms (SNPs)

The most common type of genetic variation among individuals, occurring when a single nucleotide (A, T, C, or G) in the DNA sequence is replaced by another at a specific position in the genome.

Microsatellites

Small segments of repetitive DNA where a sequence of 1 to 6 base pairs is repeated multiple times in a row.

Protein Structure and Function

Changes in the DNA sequence can alter the amino acid sequence of proteins, impacting their structure, stability, or function.

Gene Expression Regulation

Mutations in regulatory regions (e.g., promoters or enhancers) may alter the level or timing of gene expression.

Sickle Cell Anemia

A point mutation in the HBB gene causes the formation of abnormal hemoglobin, resulting in altered red blood cell shape and function.

Cystic Fibrosis

Caused typically by a deletion mutation in the CFTR gene leading to dysfunctional chloride channels.

p

Short arm of a chromosome.

q

Long arm of a chromosome.

del

Deletion (e.g., del(5p) means a deletion on the short arm of chromosome 5).

dup

Duplication (e.g., dup(7q) means a duplication on the long arm of chromosome 7).

inv

Inversion (e.g., inv(9) means a segment of chromosome 9 is flipped).

ins

Insertion (eg., ins(3) means an insertion within chromosome 3)

+

gain of (eg., +21 means trisomy 21)

-

loss of (eg., -21 means monosomy 21)

t

Translocation (e.g., t(9;22) means a segment of chromosome 9 has swapped places with chromosome 22).

trisomy

An extra copy of a chromosome (e.g., trisomy 21 refers to Down syndrome).

monosomy

A missing chromosome (e.g., monosomy X refers to Turner syndrome).

isochromosome (i)

A chromosome with identical arms (e.g., i(Xq) means the long arm of the X chromosome is duplicated).

r

Ring chromosome (e.g., r(14) means chromosome 14 has formed a ring structure).

Karyotype Notation

A karyotype notation like 46,XX,del(5p) can be broken down as: 46 = Total number of chromosomes, XX = Female sex chromosomes, del(5p) = Deletion on the short arm of chromosome 5 (associated with Cri-du-chat syndrome).

Down Syndrome

Caused by an extra copy of chromosome 21, leading to developmental delays, intellectual disabilities, and distinct facial features.

Turner Syndrome

Occurs in females who have only one X chromosome instead of two, resulting in short stature, delayed puberty, and infertility.

Klinefelter Syndrome

Affects males who have an extra X chromosome, often leading to tall stature, reduced testosterone levels, and infertility.

Trisomy 18

Characterized by severe developmental delays and physical abnormalities due to an extra chromosome 18.

Trisomy 13

Results in severe intellectual disabilities and physical defects due to an extra chromosome 13.

Cri-du-chat Syndrome

Caused by a deletion on chromosome 5, leading to intellectual disabilities and a distinctive high-pitched cry.

Angelman Syndrome

Caused by a deletion or mutation in the UBE3A gene on chromosome 15, leading to severe developmental delays, speech impairment, and hyperactivity.

Rett Syndrome

Caused by mutations in the MECP2 gene on the X chromosome, almost exclusively seen in females, causing loss of purposeful hand movements, speech regression, breathing irregularities, and seizures.

Williams-Beuren syndrome

A rare genetic disorder caused by the deletion of about 26-28 genes on chromosome 7, leading to broad forehead, full cheeks, small jaw, and upturned nose.