We have compared the sequence of the 5′ hypersensitive site-2 (5′-HS-2) of the locus control region (LCR) from a sickle cell anemia (SS) patient homozygous for haplotype 19 and with low levels of fetal hemoglobin (HbF), with the same sequence from an SS patient homozygous for haplotype 3 and with high levels of HbF. Several nucleotide variations were present in the 5′HS-2 of the haplotype 19 individual. One is the A----G at position -10905 that creates an Sp1 binding site GCCCC (A----G)CCCC. A second is the T----G at position -10924 in a sequence that binds both erythroid and ubiquitous factors and exhibits high homology to the long terminal repeat of the Moloney leukemia viruses and Friend murine leukemia virus. Other differences were in the two AT-rich stretches of DNA, and an A----T substitution at position - 10390. Dot-blot analyses of amplified DNA from several SS patients showed that these variations are specific for beta S chromosomes with haplotype 19. We also examined the 5′HS-2 sequence from an SS patient who is homozygous for haplotype 19, but has abnormally high levels of HbF (greater than 20%). We observed a cross-over that has placed sequences similar to the 5′HS-2 of haplotype 3 in juxtaposition to the 5′ flanking regions of haplotype 19. Thus, a beta S chromosome with haplotype 19 but having a 5′HS-2 (LCR) characteristic for haplotype 3 is associated with high gamma-chain expression. We postulate that factors produced under conditions of hematopoietic stress, together with genetic determinants on the haplotype 3-like LCR sequences, allow for high level expression of gamma-globin genes.

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The nondeletional types of hereditary persistence of fetal hemoglobin (ndHPFH) concern the continued synthesis of hemoglobin (Hb) F with either G gamma or A gamma chains in amounts varying from 5% to 30%. Several mutations have been identified in either the A gamma or G gamma promoter which are considered causative to the continued production of one of the two gamma chains because the substitutions occur in sequence motifs essential for the expression characteristics of the gamma-globin gene in the 3′ position. We report the discovery of a T----C mutation at position -175 in the A gamma promoter which was associated with a greatly increased level of Hb F (with mainly A gamma) and a decreased level of Hb A in the one (Black) heterozygote who had a beta c gene in trans. The same mutation has been observed in the G gamma promoter of a Black heterozygote who had high levels of Hb F with G gamma chains only. A detailed comparison between these two individuals indicated significant differences in the levels of Hb F and Hb A which may result from an additional mutation at position -158 in the G gamma promoter.

While mangrove restoration efforts are reasonably successful, failure often occurs in high wave energy situations. Due to differences in wave energy, seedling mortality rates vary strongly with position on the intertidal flat between high water spring and high water neap elevations. However, a local positive feedback can be present between the pneumatophores of adult mangroves and the survival of mangrove seedlings to trigger recovery. In this study, a mangrove population of Avicennia marina is modelled to determine the effects of seedling mortality and local positive feedback on mangrove recovery. The model uses life history data and dispersal to simulate population dynamics. The mangrove range limits are determined by high water spring and high water neap levels. The results indicate that within these limits mangrove populations with life-history parameter values as derived from literature are indeed capable of fast growth under conditions with low seedling mortality. Local positive feedback has then a small positive influence on population recovery after mangrove loss. If, however, mortality rates increase, such as in high wave energy situations, the importance of a positive feedback increases. The model shows that a positive feedback may, given high seedling mortality rates, be an important factor for mangrove recovery. While a positive feedback may enable mangrove persistence in unfavourable conditions, destruction of adult mangroves can remove the positive feedback, which would render the system uninhabitable and practically prohibits reforestation of such areas. The model results and the presence of positive feedbacks and their importance for population dynamics in harsh conditions indicate that investigating and understanding possible feedbacks could be crucial for successful restoration efforts.

In hereditary persistence of fetal hemoglobin, Hb F (alpha 2 gamma 2) is elevated after birth. Screening of sickle cell patients has revealed a family with elevated Hb F and high A gamma values. The propositus was a sickle cell patient with approximately 25% Hb F and 68.4% A gamma. He was heterozygous for the Benin (#19) and Mor beta S haplotypes. Five AS relatives with the Mor haplotype had 2.5% +/- 0.9% fetal hemoglobin and 92.8% +/- 2.8% A gamma, whereas two with the Benin haplotype had normal fetal hemoglobin (0.5%). The Mor haplotype is thus associated with the elevated Hb F in this family. The 13-kilobase (kb) Bg/II fragment containing the G gamma and A gamma genes of the Mor haplotype was cloned, and the G gamma and A gamma promoters sequenced from -383 to beyond the Cap sites. The Mor G gamma gene was normal, but the A gamma gene had a unique C----T mutation at -202. A different mutation at -202 of G gamma (C----G) was previously detected by other researchers in association with considerably higher Hb F in AS cases (15% to 25%). These data suggest either that -202 mutations affect the G gamma and A gamma promoters differently or that different nucleotide substitutions at -202 have divergent effects. Alternatively, additional unknown mutations could cause the differences in gene expression.