Intro to genetics

What is Genomics?

is the study of the entire genome of a given organism, focusing on understanding the structure, function, evolution, and mapping of genomes.

Phenotypic differences

The majority of the genome is conserved = equal in different individuals

A small percentage less than 1% of the genome is variable in unrelated individuals

Related individuals and Variable genome differences

Identical twins: share 100% of VG

Parent/Child/ Sibilings: 50%

Grandparent/Grandchild: 25%

1st degree cousins: 12.5%

How does familial genome differ?

The genomic variability is even smaller because individuals inherit most of their DNA from their parents, resulting in less genetic variation within families.

Genotyping

refers to determining which variants are present in a person’s genome. This involves identifying the variable portions of the genome, where individuals differ.

Types of genetic variants

1- Single Nucleotide Variants (SNVs)

2- Structural Variants

3- Frequency of Variants

What are SNVs?

Single Nucleotide Variants are small changes in the DNA sequence sequence and they make up to 99.9% of genetic varaints in humans.

There are two types:

• SNPs

• Indels

What is the most common type of SNV?

SNPs (Single Nucleotide Polymorphisms) are the most common form, where a single base is replaced by another (e.g., A → T or C → G).

What are indels?

are small insertions or deletions of nucleotides.

Structural Variants, what are they?

These are large-scale genetic changes and are much rarer than SNVs.

What are examples of structural variants?

• Large insertions/deletions (indels).

• Copy number variants (CNVs): DNA segments that are repeated a different number of times in different individuals.

• Inversions: DNA segments are flipped in orientation.

• Translocations: reloaction of the sequence to another chromosomal region

• Gene and chromosome deletions/duplications.

What is MAF?

Minor allele frequency = frequency of the minor allele in the general population

Variants can be classified based on their frequency in the population

• Common variants: The minor allele appears in more than 1% of the population.

• Rare variants: The minor allele appears in 0.1 to 1% of the population.

• Very rare variants: Only found in a very small number of individuals, less yhan 0.1 possibly just one family globally.

Coding variants

occur in exons of protein-coding genes and can result in amino acid changes, directly impacting protein structure and function.

• Alteration in amino acid sequence

• premature termination (truncation of protein)

• Alteration in splicing

Non-coding Variants

occur in introns of protein-coding genes or intergenic regions = non-protein coding regions of the genoem.

• Introns are transcribed into RNA but do not code for protein. They are spliced out of the final mRNA.

• Intergenic regions lie between genes and may have unknown functions, though some may play roles in gene regulation.

• Many non-coding variants are silent (non-pathogenic), while others may affect gene expression and lead to phenotypic variability.

Mutuation

a permanent alteration or change in comparison with a reference (or wild type) DNA sequence.

Non-pathogenic Variants

• Changes in DNA sequence that do not have an impact on disease, they may or may not have an impact on the phenotype. They may be common or rare in the general population.

Pathogenic Variant

Changes in the DNA sequence that have an impact on disease (large effect). Rare in the general population

Risk variants

Changes in thr DNA sequence that may have an impact on disease. They are not causative of disease, but they increase the overall risk of disease (small effect). Risk varriant usually commone.

Dominant Variant

Only one copy of the mutated allele is required to manifest the phenotype (e.g., a disease).

Recessive variants

Both copies of the allele must be mutated for the phenotype (disease) to appear. Individuals with only one mutated allele are carriers and do not exhibit the disease.

Compound heterozygotes

Inheriting two different forms of the mutant allele.

Why is the study of genetic variability important?

helps us understand diseases, as it allows us to identify variants associated with various conditions. These insights are useful for diagnostic applications, where genetic testing can confirm or rule out certain diseases.

Molecular diagnosis:

A common tool to confirm or exclude a genetic condition. When a person shows symptoms of a disease, molecular tests can identify the presence of disease-associated variants.

What are three genetic tests that are done in Reproductive health?

a. Prenatal Diagnosis:

b. Pre-implantation Genetic Diagnosis (PGD):

c. Carrier Testing:

What is Prenantal Diagnosis ?

• Conducted during pregnancy on the fetus to detect genetic conditions.

• Identifies variants associated with specific disorders.​

Pre-implantation Genetic Diagnosis (PGD)

• Performed on early embryos during in vitro fertilisation (IVF).

• Allows selection of embryos without mutations linked to serious genetic conditions for implantation.​ Thus decreases the chance that the embryo implanted in the uterus will have a serious genetic condition.

Carrier Testing:

• Conducted on prospective parents before conception.

• Determines if individuals carry variants associated with certain diseases.

• Facilitates preconception counseling to assess the risk of having an affected child.​

What are companion diagnostics?

Genetic test carried out by a medical devide, often an in-vitro device, that is essential for the safe and effective use of a corresponding drug or biological product.

Helps to identify patients who will benefit from a specific therapeutic drug, ensuring targeted treatment based on genetic makeup.

What is Cystic Fibrosis ?

CF is an autosomal recessive disorder; individuals must inherit two defective copies to manifest the disease .​

Caused by mutations in the CFTR gene, which codes for a chloride channel protein in the apical memebrane of exocrine epitheilal cells.

The vast majortiy of mutations are SNPS and indels in the CFTR gene. Usually rare

How does CF progress?

Thick, sticky mucus causes progressive damage to the respiratory system and chronic digestive system problems.

Over time, mucus builds up and infections lead to permanent lung damage, including the formation of scar tissue (fibrosis) and cysts in the lungs.

Diagnosis

• Initial clinical evaluation followed by molecular testing to confirm CFTR mutations.

• CF can be detected through prenatal diagnosis and carrier testing in families with a history of the disease.

To be affected by CF, you must have:

• 2 pathogenic mutations of the CFTR gene

  • 2 copies of the same CFTR pathogenic mutation (homozygos)

  • 2 different CFTR mutations, both of them pathogenic (compound heterozygosis)

Forensic Applications

a. DNA Fingerprinting

• Technique used to identify individuals based on unique patterns in their DNA.

• Focuses on Short Tandem Repeats (STRs), which are repeating sequences in the genome.​ The number of repeats is variable in different individuals.

b. Multiplex PCR:

• Allows simultaneous amplification of multiple STR regions in a single reaction.

• Primers work specifically on the intended STR, multiplex, because they are all amplified in one tube simultaneously.

• Enhances efficiency in forensic analyses and paternity testing.​

c. Paternity Testing:

• Compares STR profiles of the child, mother, and alleged father.

• Calculates a paternity index to assess the likelihood of a biological relationship.​

Precision Medicine

• Tailors medical treatment to individual genetic profiles.

• Genetic variability affects drug metabolism (pharmacokinetics) and drug targets (pharmacodynamics).

• Informs drug selection and dosing to enhance efficacy and reduce adverse effects.

Pharmacogenomics

Study of individual genetic variability focusingon the effects it has on drug efficacy and possible generation of ADRs and side effects.