Genetics Study Guide Intro to Genetics/ Genetics Vs Genomics

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Genetics Study Guide
Intro to Genetics/ Genetics Vs Genomics

Human genetics: study of biological variation in humans

Medical genetics: study of human biological variation as it relates to health and disease

Clinical genetics: provision of comprehensive diagnostic, management, treatment, and counseling services to individuals and their families

Genetic vs. Genomic

Prior to the Human Genome Project, Medical Genetics primarily focused on genetics (study of genes and role in inheritance; ways traits are passed from one gen to the next) Now due to human Genome project have entered era of Genomics (study of an individuals genome including interactions of those genes with each other and with the person’s environment. Genomics includes the scientific stud of complex diseases lie obesity, asthma, cancer etc) New promise for therapies and treatments as well as new diagnostic methods

Genomics in involved in almost all disease except trauma, even involved in viral susceptibility.

Making transition from treatment of sick to preventative care

Human Genome project

GOAL: Sequence human genome, identify cause and genetic component of human disease and provide diagnostic tests, which would eventually lead to better treatments and cures


  • Identified genome contains 3 bil base pairs

  • 25,000 genes

  • Discovery of 2500 disease causing genes

  • Advance process of disease gene ID (decreased time from years to days)

  • 350 biotech projects

  • Hap Map project- 11 global populations to identify and catalog human gene variation (genetic similarities and differences)

    • Based on “common disease, common variant” hypothesis

    • Sped the discovery of genes related to common illness like cancer, asthma etc.

    • Study genetic factors contributing to variation in response to environmental influences, susceptibility to infection, and effectiveness of drugs and vaccines

    • Database of human variants

  • Lead to dev of ethical legal and social implications (ELSI)

    • Privacy

    • Clinical integration of genomic tech

    • Fairness in used of genetic info

    • Public and professional training of these issues

  • Lead to ENCODE-encyclopedia of DNA elements

    • Comprehensive catalog of all components of the human genome crucial for biological fxn

    • Discovered that majority of DNA is human genome is transcribed into fxnl RNA and that transcripts extensively overlap one another. No longer junk DNA. Genome contains very little unused sequence. Many other elements besides just genes

    • Contains switches to regulate which genes are used in a cell and when they are used and determine cell type

Future Goals

  • Cancer Genome Atlas

  • 1000 genome project- sequence 2500 individuals to catalog at least 90% of most common genetic variations

  • Rare disease project

  • Target interventions and gene therapy

  • Personalized medicine

How does human genome project affect current and future health care?

GWAS (Genomic wide association studies)

  • Scan genome for genetic variants for specific diseases (useful to identify variants in complex diseases such as asthma, obesity etc

  • HGP and hapmap paved way for GWAS by providing tools and tech

    • Database that contain reference human genome sequence

    • Map of human genetic variation

    • New technologies that can quickly and accurately analyze whole genome samples for genetic variations that contribute to onset of a diseases

  • First success was identifying a variant in complement factor 4 in macular degeneration

GWAS lead to consumer genetic testing (23andMe 99 dollars, FDA banned because failure to comply with previous inquires regarding potential public health risk of false negative or false positive that lead patients to improper care. Now only provides info on ancestry.

What every health professional should know:

  • Family history #1 tool for genomic disease

  • Understand general genetics terms

  • Know diseases common to specific ethnic groups

  • Understand social, ethical, and legal issues surrounding genetics

  • Understand how environmental, behavioral and genetic factors play into disease

  • Know the resources available to assist clients seeking genetic information or services, including types of genetics professionals available and their diverse responsibilities

Role of genetic professionals:

Clinical geneticist= physician, diagnosis, treatment, management, risk assessment, counseling for diagnosed or at risk individuals with genetic components to their disease

Genetic counselor= assists to help people understand their disease. Use family and medical histories to Asses risk and recurrence chances. Provide info about testing and management of disease. Counseling to help promote informed choices and adaptation to risk or condition (masters)

Laboratory specialists= PhD, MD, DO lead clinical laboratories and provide genetic testing

Clinical Biochemical geneticists= specialize in treatment of patients with inborn errors of metabolism (1 yr fellowship from medical genetics residency)

Chromosomal nomenclature and structure

Band pattern is numbered according to convention from the centromere to the terminal portion of the short (p for petite) arm and long (q) arms.

Metacentric=centromere in middle

Acrocentric=centromere near one end, leading to short p arms which end is structures called satellites

  • 13, 14, 15, 21, and sometimes Y (not involved with robersonian, no satellites, pairs with X via pseudoautosoal region in short arm, numerous Y autosome translocations)

  • robertsonian translocations

  • Satellite (short arm) codes for ribosomal RNA

Sub-metacentric= centromeres BW two extremes

Band= part of chromosome that is clearly distinguishable from its adjacent segments by appearing darker or lighter by 1 or more banding techniques

Ideogram= individual chromosomes identified and aligned in pairs based on accepted standard nomenclature

Mainly use G banding=

  • stain positive for Gimesa

  • 400-500 total bands on average

  • Dark bands=more highly condensed, less transcriptionally active genes such as those expressed at specific times during development (i.e. tissue specific)

  • Light bands= less condensed, more euchromatin (unique copy DNA), and location of more transcriptionally active genes involved in the day to day activities of the cell (housekeeping genes)

Classification of banded chromosomes/nomenclature

  • Landmark= consistent and distinct morphologic feature that is useful and important in identifying a particular chromosome (most prominent on G band)

  • Region= area between two landmarks

  • Identifying a band: chromosome #, arm designation (p,q, tel), region number, band number with in that region, period and then subregion

  • Region numbers sequential, moving outwards from centromere along length of chromosome arm

  • When band bisected by centromere it is considered as 2 band and labeled as band 1, region 1 of each arm

  • Up to 9 subregions within a major band

  • Ex: 8q21.3

High resolution banding:

  • Uses compounds that interfere with condensation leading to longer chromosomes (prophase or pro-metaphase) 800-1200 bands total

Meiotic nondisjxn in meiosis I= gamete will contain extra chr copy and one copy will be maternal while other is paternal

Meiotic nondisjxn in meiosis II= gamete will contain extra chr copy and both copies will be identical (i.e. both paternal, both maternal)

Mitotic nondisjxn= would result in mosacism

Structural abnormalities

  • 1 chromosome

    • Duplication/ deletion- doubling or loss of chr material can either be at end of chr or w/in chr (terminal vs. interstitial)

    • Inversions=2 breaks in one arm (paracentric) or one break in each arm (pericentric), reversal of orientation bw breaks

    • Isochromosome= complete absence of one of the chromosome arms, with complete duplication of the other chromosome arm

  • 2 chromosomes

    • Insertions- need at least 3 breaks in 2 chromosomes

    • Translocation/exchange of chromosomal material

    • Balanced= no essential chromosomal material is lost and not genes are damaged during breakage and reunion (equal exchange), clinically normal, but increase risk to have offspring with an unbalanced amount of chromosome material

  • Reciprocal translocation= exchange of chromosome material bw non homologous chromosomes (can be balanced, unbalanced, partial trisomy and partial monosomy (extra copy of one segment and deletion of other segment)

  • Unbalanced gametes are usually unviable (embryonic loss/ spontaneous miscarriage)

  • Robertsonian= a translocation BW two acrocentric chromosomes by fusion at the centromere with loss of the short arm and satellites. Because the short arms of all five pairs of acrocentric chromosomes have multiple copies of genes for ribosomal RNA, loss of short arms of two acrocentric chromosomes is not deleterious.

Gene Structure

Boundaries b/w introns and exons begin w/ GT and end with AG

ATG= universal translation intiation codon

Termination codon= TAA,TAG,TGA

Promoters include: TATA, CCAT boxes

Enhancers= more disant to gene, may be involved in tissue specific instruction

Nucleotide “1” is the A of the intiation codon, anything 5’ of this is (-) and anything 3’ is (+)

Nucleotides more 3’ to the translation stop is *1, *2 etc.

Beginnning of intron= last nucleotide of preceding exon + and position of intron

Ex: c.78+2A

End of intron= first nucleotide of following exon(-) and position of intron

Ex: c.78-2A

Genetic locus= position or location of a gene, defined by chromosomal loaction or molecular marker

Allele= version of the gene that is present at any given locus, each allele has a specific and unique nucleotide sequence


Goal of identifying mutation: understand normal by understanding abnormal

Change in DNA sequence may or may not lead to a change in amino acid sequence and may or may not be pathogenic

  • be careful when using the word “muation” with parents or patients—may imply a negative conotation

  • polymorphism: a sequence change seen in more than 1% of the poulation, relatively common change and unlikely to be pathogenic

  • sequence variant

    • known=usually benign

    • unknown significance?

Point muation= single base pair change in DNA

  • silent= does not change aa, usually not pathogenic

  • missense= susbstitues one amino acid for another, may or may not be pathogenic

  • nonsense= creates a stop codon in place of an aa, always pathogenic; degree of pathogenicity depends on location of stop codon

Splicing= distupt the consensus splice site sequence or create alternative site. Expected to be pathogenic

Small inserions/deletions= will change reading frame if in coding region and not in multiples of 3, ie frameshift and expected to pathogenic. If 3 base in/del you are not shifting reading frame but still removing/ adding an amino acid codon

Trinuclotide repeat expansion like fragile X and huntingtons

Naming mutations:

  • nuclotide level c.2983G>A (c means reference sequence, > means switch to)

  • protein level C282Y (cystine replaced with tyrosine) or W1282X (replaces amino acid with stop codon)

muations lead to synthesis of abnormal protein, decreased amounts of protein or no protein

DNA sequence for each allele a person carries must be different in order to be informative

Chromosomal Anomalies

50% or more of miscarriages from recognized pregnancies contain major chromosomal abnormalties

earlier in gestation loss occurs, greater likelyhood that is is chromosomal abnormal

triosomy 16 never reported in a liveborn infant, but frequently seen in spontaeous abortion


Inheritance & Abnormality



Trisomy 21

(Down Syndrome)

  • Chromosomal Anomaly

    • Nondisjunctional trisomy (more likely with greater maternal age) (95% cases, 80% of these are meiosis I error) (only 5% are paternal in origin)

    • Mosaicism (1%) (Not necessarily less severe)

    • Translocation (4%) (Not associated with maternal age)

  • Recurrence Risk

    • General – 1%

    • If balanced translocation carrier

  • 9% babies born to women less than 35 yrs have unbalanced translocation and less than 2% born to women older than 35

  • 50% of translocation cases are inherited from a carrier parent

    • Carrier mother – 10-15%

    • Carrier father – 5%

    • Balanced 21:21 translocation – 100%

*Note= risk for chromosome aneuploidy is generally twice the risk of that reported for down syndrome because majority of monosomies and triosomies are lost in early pregnancy and only a relative few attain viability during the pregnancy and of those that do ½ are down syndrome

*80% of children with down syndrome are born to women under 35 because more children are born to women under age 35

  • Slanted palpebral fissures (upward slanting)

  • Poor moro reflex

  • Anomalous ear auricles

  • Hyperflexiblity of joints

  • Dysplasia of pelvis

  • Dysplasia of midphalanx of 5th finger

  • Single palamar (simian) crease

  • Depressed nasal bridge and small nose (flat face)

  • Excess skin on back of neck

  • Hearing & Vision impairment

  • Slower development

    • Developmental milestones delayed

  • Mental retardation (mild to moderate)

  • Congenital Heart Defects (major mortality)

  • Duodenal atresia

  • Hypotonia (muscle tone tends to improve with age)

  • Males have low fertility potential, likely secondary to low serum testosterone

Best outlook:

Normal family life in own their own home

Schools required to provide services
Prenatal diagnosis is available for couples who already have a child with down syndrome


Trisomy 21

Trisomy 18

(Edward Syndrome)

  • Second most common multiple malformation syndrome

  • 3:1 ration males to females

  • Chromosomal Anomaly

    • Nondisjunctional trisomy (greater frequency in advanced maternal age)

    • Translocation (very rare)

  • Recurrence Risk

    • Nondisjunction: 1% or less

    • Lower than trisomy 21 bc most die in early embryonic or fetal life-spontaneous abortions

    • Translocations only excluded by chromosomal study of infant, determine if balanced carrier

    • Moscasism results in longer survival and variable expression

  • Before Birth

    • Polyhydraminos

    • Decreased fetal activity

    • Single umbilical artery

    • Growth retardation

  • At Birth

    • Hypertonia

    • Microcephaly

    • Low-set malformed ears

    • Micrognathia (small jaw)

    • Cleft lip/palate

    • Clenched fist (index and little finger overlapping)

    • Rocker bottom feet

    • Hypoplastic sternum (missing 12th ribs)

    • Inguinal or umbilical hernia, mekels diverticulum, omphalocele, malrotaiton of the bowel

    • Horseshoe kidney

    • Diaphragmatic hernia

    • Cardiac defects

Limited capacity for survival, resuscitation at birth, panic episodes in neonatal period

Failure to thrive is from associated feeding problems and poor sucking capacity

30% die within 1 mo 50% by 2 mo and only 10% survive first year as infants with server mental retardation

Limitation of medical intervention to prolong life is generally offered as an option


 Trisomy 18

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