Basics in Genetic Control of Inheritance
Genetic information is stored on chromosomes, of which there are 23 pairs in each
human cell. 22 pairs are autosomes, and they are numbered when arranged by size
and shape in a diagnostic graphic termed a karyotype. The 23 pair consists of the pair
of sex chromosomes; males have XY, and females have XX.
Short arm: p (petite)
Long arm: q
The chromosomes are made up of many genes, which are matched for a function
(allele) at a specific location on the paired chromosomes. All cells in an individual’s body
contain the same chromosomes and genes for the same traits (genotype), although not
all genes are active in each cell.
When a specific gene for a pathologic condition is identified, a DNA analysis follows with
the hope for the development of a simple blood test to screen individuals for the
presence of that specific gene.
During meiosis (gametogenesis), each human sperm and ovum receive only 23
chromosomes, that is, one chromosome from each pair (haploid). When the ovum is
fertilized by the sperm, the resulting zygote has 46 chromosomes, or 23 pairs (diploid)
containing an assortment of genetic information inherited from the parents.
During embryonic and fetal development, when cells undergo mitosis, the chromosomes
replicate, and each daughter cell receives a copy of DNA identical to that in the parent
cell carrying forward the same genetic information.
Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care
Infant DNA tests speed diagnosis of rare diseases
About one in 20 babies in newborn intensive care units has a genetic disease, and all
too often, no one can figure out what it is.
Scientists identified the faulty genes for about 3,500 of 7,500 known genetic diseases;
about 500 have treatments.
With the new method, a computer program searches for genes based on the baby’s
symptoms. And because it focuses only on genes that cause diseases in newborns, it
avoids an ethical problem: findings that are unrelated to the problem at hand. In
sequencing and analyzing the entire DNA, researchers may discover, for example,
aberrations leading to conditions that occur only in adults. The method is expensive, though, costing about $13,500. It is not yet covered by
insurance. It should be cost effective for insures as each day a baby spends in intensive
care costs about $8,000, so any test that reduces that time would quickly pay for itself.
A close look at how gametes form
Homologous chromosome pairing
Meiosis I: crossing over and random distribution of chromosomes during the first
meiotic division contribute to the enormous genetic variability of the daughter
Meiosis II: works as mitosis
Four haploid cells
Compare to mitosis
Mitosis: chromosomes line up in center, pulled to ends
Two diploid cells
Congenital anomalies refer to disorders present at birth
Such defects include genetic or inherited disorders as well as developmental disorders
(often do not have a genetic component)
Genetic changes can occur because of an error in the process of meiosis or mitosis.
Such a mutation or alteration in genetic material – e.g. transition, transversion, deletion,
substitution – may occur
May result from exposure to harmful substances such as radiation, chemicals, or
Genetic disorders may result from
A single-gene trait or
A chromosomal defect (numerical and/or structural) or
Polygenic traits Polygenic traits are determined by multiple genes located on more or
E.g., eye color, finger prints
Multifactorial inheritance represents the additive effects of many abnormal
genes and environmental factors
Multifactorial disorders tend to run in the families
E.g., obesity, hypertension, atherosclerosis, diabetes
Autosomal dominant diseases usually affect structural proteins and receptors whereas
many autosomal recessive gene disorders involve an enzyme deficit
Mutations of single genes in the body cells other than the reproductive cells may cause
dysfunction but are not transmitted to offspring. In some cases, the expression, or effect
(phenotype), of an altered gene produces clinical signs that vary in severity depending
on the penetration or activity of the gene.
Single-gene disorders are caused by a change in one gene within the reproductive cells
(sperm or ova); this mutant gene is then transmitted to subsequent generation, following
the specific inheritance pattern for that gene.
Mendelian traits (single gene defects) reflect the expression of two copies
(alleles) of the same gene present on homologous chromosomes.
Mendelian traits may be caused by the inheritance of one or both defective
alleles, depending on the nature of the gene product.
The most important forms of Mendelian inheritance are
Autosomal dominant traits require the expression of only one allele of a
homologous pair (i.e., the phenotype is present when alleles are
heterozygous or homozygous.)
E.g. familial hypercholesterolemia, adult polycystic kidney
disease, hereditary elliptocytosis and spherocytosis,
neurofibromatosis type I, Ehlers-Danlos syndrome, von Willebrand
disease, familial adenomatous polyposis coli, Marfan syndrome,
osteogenesis imperfecta, achondroplasia
Autosomal recessive traits require the expression of both alleles of a
homologous pair (i.e., the phenotype is present when alleles are
E.g. sickle cell anemia, thalassemia, hereditary hemochromatosis,
Gaucher disease, myeloperoxidase deficiency, cystic fibrosis Sex-linked traits
Sex-linked recessive traits are most commonly seen in heterozygous males (46,
XY) who lack the matching normal gene on Y.
A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits
to their sons.
X-linked recessive disorders require the expression of both alleles on the X-
chromosome (i.e., the phenotype is present in females only when X-linked alleles
are homozygous [In heterozygotes, random X-inactivation results in mosaics
leading to variable phenotypic manifestations.])
E.g. Duchenne-Becker muscular dystrophy, Hemophilia A (factor VIII
deficiency), Lesch-Nyhan syndrome (HPRT deficiency), color blindness
X-linked dominant disorders affect both males and females
E.g. fragile X syndrome, the most common cause of learning disorders,
cognitive deficit and mental retardation in North America. The mutation
causes the affected X chromosome to appear constricted or broken.
X-Inactivation and Dosage Compensation
Given that mammalian females have two X chromosomes and males one,
humans and most other mammals have evolved a means of dosage
compensation to correct for the expected effect of 2 X chromosomes vs. one.
One X becomes inactive (not totally) – Barr body
X-inactivation is random
In any cell, initial inactivation (at blastocyst stage) may affect either the X
transmitted by the father or the X from the mother.
The pattern is then fixed and is passed on to all daughter cells throughout mitosis
and development; thus females are mosaics regarding X-linked gene expression.
This biologic mosaicism has important impacts on phenotypic expression for X-
linked traits in heterozygous females.
Numerical or structural abnormalities of autosomes or sex chromosomes
Chromosomal anomalies usually result from an error during meiosis
When the DNA fragments are displaced or lost, thus altering genetic information,
e.g., a form of Down syndrome. This may be spontaneous or result from
exposure to a damaging substance.