Chapter 2: Evolution of CG and development of humans

Chorionic gonadotropin (CG) first evolved with Callicebus 37 million years ago. It evolved by a deletion mutation of the luteinizing hormone (LH) ß-subunit. Mammals generally fed fetuses thought epitheliochorial placentation, a very inefficient system, as such brain growth genes could not function, and mammals generally had very small brains (Table 2.1) [1-3]. The only exception to this fetal feeding limitation, or brain size problem, was dogs and cats that used zonary fetal feeding. Epitheliochorial placentation was grossly inefficient requiring nutrients to cross multiple layers of cells and the placenta-uterine space (Fig. 2.1).

Table 2.1

Brain size of mammals. Mammal Placentation Body weight (g) Brain weight (g) Brain to body mass ratio (%) 1. Minimal brain mammals     African elephant Epitheliochorial 6,654,000 5,712 0.09     Humpback whale Epitheliochorial 36,000,000 4,675 0.13     Sperm whale Epitheliochorial 57,000,000 7,800 0,14     Dolphin Epitheliochorial 500,000 1,500 0.30     Asian tiger Epitheliochorial 167,000 263 0.16     Cow Epitheliochorial 465,000 423 0.09     Giraffe Epitheliochorial 529,000 680 0.13     Grizzly bear Epitheliochorial 261,000 450 0.17     Horse Epitheliochorial 490,000 784 0.16     Donkey Epitheliochorial 187,000 419 0.22     Jaguar Epitheliochorial 100,000 157 0.16     Kangaroo Epitheliochorial 35,000 56 0.16     Leopard seal Epitheliochorial 400,000 542 0.14     Lion Epitheliochorial 200,000 360 0.18     Manatee Epitheliochorial 475,000 360 0.08     Pig Epitheliochorial 192,000 180 0.09     Polar bear Epitheliochorial 390 0.498 0.13     Rat Epitheliochorial 380 0.418 0.11     Sheep Epitheliochorial 140,000 160 0.11     Squirrel Epitheliochorial 500 0.50 0.10     Asian Tiger Epitheliochorial 250,000 450 0.19     Zebra Epitheliochorial 300,000 250 0.08     Mean 0.13 2. Larger Brain mammals     Dog Zonary placentatio 20,000 160 0.80     Cat Zonary 1,400 13 0.90     Mean 0.85 3. Early primates     Tarsier Epitheliochorial 1,473 1.04 0.07     Lemur Epitheliochorial 2,200 1.5 0.07     Mean 0.07 Figure 2.1 Epitheliochorial placentation. Everything changed with the evolution of CG, the introduction of CG promoting hemochorial placentation, a new much more efficient form of fetal feeding. As shown by Fiddes and Goodman [4], CG ß-subunit evolved in Callicebus by a deletion mutation in the LH ß-subunit gene (Fig. 2.2). As shown, the deletion mutation led to read through of the TAA stop codon on the LH ß-subunit gene (Fig. 2.2), and the generation of a 145 amino acid versus 121 amino acid ß-subunit. The CG ß-subunit combined with the common a-subunit glycopeptide to form CG. Figure 2.2 The deletion mutation in Callicebus LH ß-subunit. Hemochorial placentation is best described by an illustration of human hemochorial placentation (Fig. 2.3). A central chamber composed of villous cytotrophoblast cells forms the villous core, or fetal storage tank. Nutrients must pass over a single layer of fused syncytiotrophoblast that surrounds the villous core to get into the villous core. The syncytiotrophoblast is surrounded by a tank of maternal blood. The villous core is attached to the uterus through a plug of extravillous cytotrophoblast cells. Figure 2.3 Human hemochorial placentation. Figure shows one chamber, in life there is 4-6 chambers in the placenta. The first CG was made from LH and had a very a basic, isoelectric point (pI) pI 8.2, producing a hormone with minimal activity. Callicebus CG had a pI of 6.3 and was also a molecule with minimal activity. It made a very minimal activity form of hemochorial placentation (Fig. 2.4). Callicebus made the hormone CG, hyperglycosylated hCG and extravillous cytotrophoblast hCG. All are required in the synthesis and implantation of hemochorial placentation. Figure 2.4 Hemochorial placentation in Callicebus, Orangutan and humans. Species beyond Callicebus, Callicebus to human, made an increasingly acidic form of CG, moving the pI up from 6.3 (Callicebus) to 3.5 (human). A form of acidic CG evolution occurred making CG stepwise more and more acidic. The more acidic molecules were rejected by the negatively charged renal glomerulus, and kept in the circulation. As such, circulating ½-life was increased with more acidic molecules and consequently biologic activity was increased with this increasing acidity. Most of the species between Callicebus and humans are now extinct. We were able to obtain data on Callicebus, evolved 37 million years ago, on Aotus, evolved 37 million years ago, on Baboon, evolved 20 million years ago, on Orangutan, evolved 12 million years ago, and on humans, evolved 0.2 million years ago. Callicebus CG (hormone CG, hyperglycosylated CG and extravillous cytotrophoblast CG) is pI = 6.3, Aotus CG is pI = 6.2, Baboon CG is pI = 5.4, Orangutan CG is pI = 4.9, and human CG is pI = 3.5 (Table 2.2). Callicebus CG is circulating ½-life 2.4 h, Aotus CG is ½-life 2.6 hours, Baboon CG is ½-life 4.7 hours, Orangutan CG is ½-life 6.0 hours and human CG is ½-life 36 hours (Table 2.2).

Table 2.2

The evolution of CG and humans. Species Family Evolved ya Sugar side chains on CG ß-subunit pI Clearance rate Depth of implantation Brain mass % body weight (vs. lemur) Homo sapiens 200,000 ya 6 sugar chains pI = 3.5 36 h 30% 2.4% (34X) Homo heidelbergensis, Hominini 400,000 ya Extinct Extinct Extinct 2.1% (30X) Homo erectus, Hominini 1,000,000 ya Extinct Extinct Extinct 1.6% (23X) Homo ergaster,...