Developmental Genetics

Dr. E. M. Honey

Department Genetics

University of Pretoria

Main events in the development of a human infant

Pre-embryonicFirst cell division 30 hours

Zygote reaches uterine cavity 4 days

Implantation 5-6 days

Formation of bilaminar disc 12 days

Lyonization in female 16 days

Formation of trilaminar disc 19 days

Closure of the neural tube 24 days

Main events in the development of a human infant

Embryonic stageOrganogenesis 4-8 weeks

Brain and spinal cord are forming 4 weeks

First sign of heart and limb buds

Brain, eyes, heart and limbs developing 6 weeks

Bowel and lungs begin to develop

Digits have appeared

Ears, kidneys and muscle are developing 8 weeks

Palate closes and joints form 10 weeks

Sexual development almost complete 12 weeks

Main events in the development of a human infant

Fetal stageFetal movements felt 16-18 weeks

Eyelids open

Fetus now viable with special care 24-26 weeks

Rapid weight gain due to growth and

Accumulation of fat as lungs mature 28-38 weeks

Tissue origins• Ectoderm Central nervous system Peripheral nervous system Epidermis including hair and nails Subcutaneous glands Dental enamel

• Mesoderm Connective tissue Cartilage and bone Smooth and striated muscle Cardiovascular system

Urogenital system

• Endoderm Thymus and thyroid Gastro-intestinal system Liver and pancreas

Genes involved in the developmental process

• Gene and gene families identified in the fruit fly

Drosophila melanogaster• Produces transcription factors - controls RNA transcription

from the DNA template by binding to specific regulatory DNA sequences

- switch genes on and off by activating or repressing gene expression

- regulating fundamental embryological processes

Genes involved in the developmental process

• Mutations in various members of these gene families can result in either isolated malformations or multiple congenital anomaly syndromes

• Examples: Segmentation genes, Homeobox genes, Paired-box(PAX) genes, SRY-type HMG box(SOX) genes, T-box(TBX) genes, Zinc finger genes, signal transduction(“signalling”) genes.

Genes involved in the developmental process

• Segmentation genes: Sonic Hedgehog, Desert Hedgehog and Indian Hedgehog

- left-right asymmetry, polarity in the CNS, organogenesis and formation of the skeleton

• Homeobox genes: 39 identified, embryo can’t survive

• Homeobox-like domain: MSX2(craniosynostosis) and EMX2(schizencephaly)

• Paired-box(PAX) genes: 9 identified

- PAX3 – Waardenburg syndrome

- PAX2 – renal-coloboma syndrome

- PAX6 – aniridia(WAGR syndrome)

Genes involved in the developmental process

• SRY-type HMG Box(SOX) genes

– role in male sexual determination

- SOX9 on Chr 17 causes camptomelic dysplasia

- SOX10 on Chr 22 causes Waardenburg syndrome associated with Hirschprung didease

• T-BOX(TBX) genes

- role in mesoderm formation and notochord differentiation

- TBX3 causes ulnar-mammary syndrome

- TBX5 causes Holt Oram syndrome

Genes involved in the developmental process

• Zinc finger genes – complex of 4 amino acids which form a complex with a sinc iron

- GLI3 on chr 7 – deletions causes Greig cephalopolysyndactily, frameshift mutations causes Pallister-Hall syndrome

• Signalling genes – implicated in cancer

- RET proto-oncogene causes Hirschprung disease

- Fibroblast growth factor receptors

Fibroblast growth factor receptors

Craniosynostosis syndromes

FGFR1 8p11 Pfeiffer

FGFR2 10q25 Apert

Crouzon

Jackson-Weiss

Pfeiffer

FGFR3 4p16 Crouzon

Skeletal dysplasia

FGFR3 4p16 Achondroplasia

Hypochondroplasia

Thanatophoric dysplasia

Limb as a developmental model

• 4 main phases: 1. Initiation – FGF 2, 4 or 8

2. Specification - HOX genes limb type

3. Tissue differentiation – SHH, HOXA, HOXD

4. Growth – FGF genes important

Sexual differentiation

• X and Y chromosomes

• SRY gene – transcription regulator

• Mutations XY females

• Crossover XX males

• Other genes plays a role e.a. SOX9