Coordinated Action of Biological Processes during Embryogenesis Can Cause Genome-Wide Linkage Disequilibrium in the Human Genome and Influence Age-Related Phenotypes

Abstract

A role of non-Mendelian inheritance in genetics of complex, age-related traits is becoming increasingly recognized. Recently, we reported on two inheritable clusters of SNPs in extensive genome-wide linkage disequilibrium (LD) in the Framingham Heart Study (FHS), which were associated with the phenotype of premature death. Here we address biologically-related properties of these two clusters. These clusters have been unlikely selected randomly because they are functionally and structurally different from matched sets of randomly selected SNPs. For example, SNPs in LD from each cluster are highly significantly enriched in genes (p=7.1×10^-22 and p=5.8×10^-18), in general, and in short genes (p=1.4×10^-47 and p=4.6×10^-7), in particular. Mapping of SNPs in LD to genes resulted in two, partly overlapping, networks of 1764 and 4806 genes. Both these networks were gene enriched in developmental processes and in biological processes tightly linked with development including biological adhesion, cellular component organization, locomotion, localization, signaling, (p<10^-4, q<10^-4 for each category). Thorough analysis suggests connections of these genetic networks with different stages of embryogenesis and highlights biological interlink of specific processes enriched for genes from these networks. The results suggest that coordinated action of biological processes during embryogenesis may generate genome-wide networks of genetic variants, which may influence complex age-related phenotypes characterizing health span and lifespan.

Keywords: Age-related traits; Embryogenesis; Functional linkage; Healthspan; Linkage disequilibrium.

Figure 1. Clustering of SNPs in genes

Solid line denotes the number of genes for SNPs from the (A) Y and (B) G reference SNP sets. Filled dots show the number of genes for SNPs from each of the random SNP sets matching the (A) Y and (B) G reference SNP sets. The differences between mean numbers of genes in random sets (dashed line) and the number of genes in the reference sets (solid line) are highly significant for the Y and G sets.

Figure 2. Averaged length of genes in the reference and random sets

Solid line denotes mean number of SNPs in genes (that is a proxy of gene length) for the (A) Y and (B) G reference sets. Filled dots show mean number of SNPs in genes from each of the random SNP sets matching the (A) Y and (B) G reference sets. The differences between mean number of SNPs in genes in random sets (dashed line) and the mean number of SNPs in genes in the reference sets (solid line) are highly significant for the Y and G sets.

Figure 3. Overlap of SNPs between the reference sets and between the random sets

Solid line denotes the number of SNPs overlapping between the Y and G reference sets. Filled dots show the number of SNPs overlapping between pairs of random sets matching the Y and G reference sets. The difference between the overlap of the reference sets (solid line) and the mean overlap of pairs of random sets (dashed line) are highly significant.

Figure 4. General biological process GO terms significantly enriched by genes from the reference Y and G sets

Embryo development encompasses the differentiation, morphogenesis and growth of cells, tissues, organs, and organ systems. The developmental processes characteristic for embryogenesis tightly cooperate with other complex, biologically important processes that drive many aspects of development. Multiple signaling events integrate the information, coordinate, trigger and ensure regulation of biological processes to correct and complete formation of fetus under various environments. Solid ovals show highly-significantly enriched processes. Although GO term metabolic process was not significantly enriched, its major sub-processes were highly significant.

Figure 5. GO terms tree for neuron development

Related higher level developmental BPs are significantly enriched (with p-values shown in the figure) by genes for SNPs from the Y set.

Figure 6. Scheme of a system of interlinked developmental processes controlled by the Wnt signaling pathway represented by the selected Y set-specific BPs

Each of the numbered specific processes was neither enriched in the G set nor in majority (18+) of the Y set related 20 control random SNP sets. The entire system was not enriched in any random set. Description. Wnt signaling is essential for various aspects of embryo development (1) such as the early placental development (2), gastrulation (3), and pattern formation, including patterning of the neural plate (4). The placenta (2) develops from embryonic (1) and maternal tissues. The labyrinthine layer (2a) of the placenta provides a vital link between the embryonic and the maternal circulatory systems. Gastrulation (3) of all vertebrate embryos involves the development of three distinct primary germ layers (5), early embryonic patterning (e.g. regionalization of neural plate (4, 4a, 4b)) and formation of the primitive gut (e.g., gastrulation with mouth forming second (6)). Mesoderm (5a) is the middle of the three germ layers. The paraxial mesoderm (5b) is an early mesoderm derivative, that contributes extensively to many adult tissues. GO term gastrulation with mouth forming second (6) highlights the origin of a through gut of bilaterally symmetric organisms that initially regionalized along A-P axis. The neural plate, the CNS primordium, lengthens along the A-P axis. Regionalization of neural plate (4, 4a, 4b) is the first step in neural patterning. The neural plate (4b) can be patterned by signals from the paraxial mesoderm (5b). The neural plate transforms into the neural tube which forms the brain and spinal cord. The neural plate is also the source of the majority of neurons and glial cells. The hindbrain (7) is a key source of patterning information and the motor innervation in the developing head. The cerebellum (7a) arises from the dorsal surface of the hindbrain (7) and plays an important role in motor control (A). Hindbrain (7) neural progenitors give rise to cranial motor neurons and astrocyte as well. Motor neurons axon guidance (8) is the process by which motor neurons send out the nerve fibers or axons to reach the correct targets. Astrocytes (9) are the most abundant glial cell type in the CNS. Astrocytes (9) contribute to axon guidance (8) and play a significant role in motor neuron survival and in cerebellar development (7, 7a). The neural plate (4b) contributes to neural crest (10) along with the underlying paraxial mesoderm (5b). The neural crest is first induced at neural plate border but then neural crest cells migrate elsewhere. The paraxial mesoderm (5b) and the neural crest (10) are both responsible for the development of the craniofacial skeleton, particularly neurocranium (11). Hindbrain-derived neural crest cells (10) and paraxial mesoderm (5b) that located superficially beside the hindbrain are the source of the pharyngeal arches (12). The pharyngeal arches develop into skeletal muscle (13) and cartilage. The cranial neural crest (10) plays an important role in patterning muscular organization (13). The unsegmented paraxial mesoderm (5b) of the head region gives rise to the head and neck skeletal muscles (13) as well. Muscle fibers are formed by the maturation of myotubes (14). Motor axons (8) contact myotubes (14) in skeletal muscles. The hindbrain motor neurons (8) innervate skeletal muscles (13) derived from the pharyngeal arches (12). Developmental relationships between these characteristic for the Y set specific processes controlled by Wnt signaling emphasizes organization in the head region and formation of basic apparatus for motor control (A). This is in line with crucial roles of Wnt signaling in synapse organization and neuromuscular junction development which occurs synchronously.